Aryl halide cross-coupling method and product made therefrom

ABSTRACT

A solid-supported catalyst ligand which chelates palladium (II) species to form a complex that functions as a heterogeneous catalyst that is stable and can be recycled without significantly losing any catalytic activity in a variety of chemical transformations, a method for producing the solid-supported catalyst ligand and a method for catalyzing a palladium cross-coupling reaction, such as the Suzuki-Miyaura, Mizoroki-Heck, and Sonagashira reactions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority from U.S. ProvisionalApplication No. 62/313,849 filed Mar. 25, 2016, the entire contents ofwhich are herein incorporated by reference.

BACKGROUND OF THE INVENTION Technical Field

The present disclosure relates to a solid-supported catalyst ligand andpalladium (II) complexes and catalyst compositions thereof.Additionally, the present disclosure relates to methods for producingthe solid-supported catalyst ligand and methods employing its complexesto catalyze chemical transformations including palladium cross-couplingreactions.

Description of the Related Art

The “background” description provided herein is for the purpose ofgenerally presenting the context of the disclosure. Work of thepresently named inventors, to the extent it is described in thisbackground section, as well as aspects of the description which may nototherwise qualify as prior art at the time of filing, are neitherexpressly or impliedly admitted as prior art against the presentinvention.

Catalytic cross coupling reactions have been recognized among the bestdirect routes for the formation of carbon-carbon bonds [G. Zhang, Y.Luan, X. Han, Y. Wang, X. Wen, C. Ding, Appl. Organomet. Chem. 2014, 28,332.—incorporated herein by reference in its entirety]. Palladiumcomplexes have been the most effective and versatile catalysts for thesynthesis of biphenyls (Suzuki-Miyaura cross coupling reactions),internal alkenes, and alkynes (Mizoroki-Heck and Sonogashira crosscoupling reactions) [H. U. Blaser, A. Indolese, A. Schnyder, H. Steiner,M. Studer, J. Mol. Cat. A: Chem. 2001, 173, 3; and G. A. Orasa, M. S.Viciu, J. Huang, C. Zhang, M. L. Trudell, S. P. Nolan, Organomet. 2002,21, 2866; and L. Yin, J. Liebscher, Chem. Rev. 2007, 107, 133; and F. X.Felpin, T. Ayad, S. Mitra, Eur. J. Org. Chem. 2006, 2679; and C. Lui, F.Bao, Q. Ni, Arkivoc xi, 2011, 60; and J. T. Guan, T. Q, Weng, G. Yu, S.H. Liu, Tetrahedron Lett. 2007, 48, 7129; and A. Komaromi, Z. Novak,Chem. Comm. 2008, 4968; and H. Huang, H. Liu, H. Jiang, K. Chen, J. Org.Chem. 2008, 73, 6037; and Z. Gu, Z. Li, Z. Liu, Y. Wang, C. Liu, J.Xiang, Catal. Comm, 2008, 9, 2154; and M. A. Casado, A. Fazal, L. A.Oro, Arab. J. Sc. Eng., 2013, 38, 1631; and G. K. Rao, A. Kumar, S.Kumar, U. B. Dupare, A. K. Singh, Organomelallics, 2013, 32, 2452; andT. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147.—eachincorporated herein by reference in its entirety]. The products of thesecross coupling reactions are extensively used in the production ofimportant industrial raw materials, pharmaceutical and biologicallyactive molecules [M. Toyota, C. Komori, M. J. Ihara, Org. Chem. 2000,65, 7110; and G. Amiet, H. M. Hugel, F. Nurlawis, Synlett. 2002, 3,495.—each incorporated herein by reference in its entirety]. The abilityof palladium complexes to function effectively as catalysts for crosscoupling reactions has been attributed to the feasible and facileinterchange between Pd(0) and Pd(II) or Pd(II) and Pd(IV). Plenty ofhomogeneous palladium complexes have been described to successfullycatalyze various cross coupling reactions with high selectivity, highactivity, and low catalyst loading. The complete removal of homogeneouscatalysts from the cross coupling products is a complex and costlyprocess, thus reducing the chances of industrial implementation sincemetal contamination in the end products is highly modulated by thepharmaceutical and related industries [V. Polshettiwar, C. Len, A.Fihri, Coord. Chem. Rev. 2009, 253, 2599.—incorporated herein byreference in its entirety].

A suitable method of overcoming the separation problem is immobilizingthe homogeneous catalyst [H. Gruber-Woelfler, P. F. Radaschitz, P. W.Feenstra, W. Haas, J. G. Khinas, J. Catal. 2012, 286, 30.—incorporatedherein by reference in its entirety]. Other than easy removal from thecoupling products, the immobilized catalyst offers the potential ofrecycling and the possibility of for use in a continuous flow reactor[K. Hallamn, C. Moberg, Tetrahedron: Asymmetry, 2001, 12,1475.—incorporated herein by reference in its entirety]. The ability toseparate and reuse the supported catalyst makes it a more viablealternative, especially from an economical point of view. As a result ofthese substantial advantages, the interest in the use of immobilizedpalladium catalysts to catalyze cross coupling reactions has beenincreasing rapidly. Although several supported palladium catalysts havebeen reported, the application of supported palladium bis(oxazoline)complex catalysts in cross coupling reactions has not been widelyexplored.

In practice, the separation of the supported catalysts from the productsis done either by decantation or by filtration. In these separationtechniques, the recovery of all the catalyst is unlikely, and thedecrease in reaction rate observed in the latter cycles of mostsupported catalytic systems is rarely due to catalyst deactivation, butrather is largely due to the inability to recover all of the catalystduring separation. Attempts have been made to simplify the recovery ofthe catalyst. These include, but are not limited to, applying biphasicreaction conditions, the use of sol gels, and membrane reactors [S. K.Karmee, C. Roosen, C. Kohlmann, S. Lutz, L. Greiner, W. Leitner, GreenChem. 2009, 11, 1052; and F. Gelman, J. Blum, D. Avnir, J. Am. Chem.Soc. 2000, 122, 11999; and L. Canatarella, A. Gallifuoco, A. Malandra,L. Martinkova, A. Spera, M. Cantarella, Enzyme Microb. Technol. 2011,48, 345.—each incorporated herein by reference in its entirety].

Another way of aiding catalyst recovery is to contain the catalysts in asemipermeable membrane. The membrane that is required for this techniqueis designed to allow easy transportation of both reactants and productsand have a pore size that guarantees retention of the catalyst. Thisdesign makes it possible to recover all of the catalyst after eachcatalytic run. The semipermeable membrane should also be compatible withall of the reaction conditions including the reactants, solvents,temperatures and pressures. The driving force in many of these reactionsis usually temperature, pressure or concentration gradient [I. F. J.Vankelecom, Chem. Rev. 2002, 102, 3779; and M. Gaab, S.Bellemin-Laponnaz, L. H. Gade, Chem. Eur. J. 2009, 15, 5450.—eachincorporated herein by reference in its entirety].

In view of the forgoing, one object of the present disclosure is toprovide a solid-supported catalyst ligand having suitable functionalityfor coordinating palladium (II) and a heterogeneous solid-supportedpalladium (II) catalyst thereof, such as a Merrifield resin supportedpalladium bis(oxazoline) catalyst. A further aim or the presentdisclosure is to provide methods for preparing the solid-supportedcatalyst ligand and solid-supported palladium (II) catalyst as well asmethods employing the solid-supported catalyst in palladiumcross-coupling reactions, such as, a Suzuki-Miyaura reaction, aMizoroki-Heck reaction, and a Sonogashira reaction, demonstratingsignificant catalytic activity and recycling ability.

BRIEF SUMMARY OF THE INVENTION

According to a first aspect, the present disclosure relates to asolid-supported catalyst ligand of formula (I)

or a salt, solvate, tautomer or stereoisomer thereof; wherein i) R₁, R₂,R₃, and R₄ are independently —H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, or an optionally substituted aryl,ii) each R₅ and R₆ is independently —H, an optionally substituted alkyl,an optionally substituted cycloalkyl, or an optionally substituted aryl,iii) X is O, NH, or S, and iv) SS is a solid support with the provisothat the solid support is not silica.

In one embodiment, the solid support, SS, is Merrifield resin.

In one embodiment, R₁ is —CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is —H,R₆ is —H, and X is O and the solid-supported catalyst ligand of formula(I) is

or a salt, solvate, tautomer or stereoisomer thereof wherein SS is asolid support with the proviso that the solid support is not silica.

In one embodiment, the solid support, SS, is Merrifield resin.

In one embodiment, the solid-supported catalyst the solid support, thesolid-supported catalyst, or both is in the form of a particle having anaverage particle size in terms of an average diameter of 1-100 μm.

According to a second aspect, the present disclosure relates to acatalyst composition or solid-supported catalyst, comprising i) thesolid-supported catalyst ligand and ii) a catalytic metal in the form ofa Pd²⁺ species having the formula PdZ₂, wherein the nitrogen atoms ofthe two oxazoline heterocycles chelate the catalytic metal and wherein Zis selected from the group consisting of —Cl, —I, —Br, —OAc, and —Otf.

In one embodiment, R₁ is —CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is —H,R₆ is —H, and X is O, the solid support, SS, is Merrifield resin, andthe Pd⁺² species having the formula PdZ₂ is PdCl₂.

In one embodiment, the catalyst composition comprises 0.15-1.5 mmol ofpalladium per gram of the catalyst composition.

According to a third aspect, the present disclosure relates to a processfor producing the solid-supported catalyst ligand, comprising i)reacting a phthalonitrile compound with halogen substitution at the4-position with a 2-aminoalcohol in the presence of a Lewis acidcatalyst to form a halogen substituted phenyl bisoxazoline ligand, ii)reacting the halogen substituted phenyl bisoxazoline ligand with apara-substituted phenylboronic acid compound in the presence of Pd²⁺ anda first base to form a functionalized diphenyl bisoxazoline ligand, andiii) reacting the functionalized diphenyl bisoxazoline ligand with asecond base in the presence of the solid support to form thesolid-supported catalyst ligand, wherein the para-substitutedphenylboronic acid has a para-substituent that is a hydroxyl, a thiol,or an amino group.

In one embodiment, the pthalonitrile compound is 4-iodophthalonitrile,the 2-aminoalcohol is 2-amino-2-methyl-1-propanol, the para-substitutedphenylboronic acid compound is 4-hydroxy phenylboronic acid and thesolid support is Merrifield resin.

In one embodiment, the Lewis acid catalyst is a metal triflate, thefirst base is an alkali carbonate, and the second base is an alkalihydride.

In one embodiment, the molar ratio of the 2-aminoalcohol to thephthalonitrile compound is in the range from 1:1 to 20:1.

According to a fourth aspect, the present disclosure relates to a methodfor a palladium cross-coupling reaction comprising reacting an arylhalide with a compound comprising a boronic acid, a terminal alkyne, oran alkene or derivatives thereof in the presence of a solvent, a base,and the catalyst composition to form a palladium cross-coupling productor derivatives thereof.

In one embodiment, R₁ is —CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is —H,R₆ is —H, and X is O, the solid support, SS, is Merrifield resin, andthe Pd⁺² species having the formula PdZ₂ is PdCl₂.

In one embodiment, the method further comprises i) separating thecatalyst composition from the palladium-cross coupling product orderivatives thereof to recover the catalyst composition and ii) reusingthe catalyst composition in at least 2 reaction cycles with a less than10% decrease in at least one selected from the group consisting of aturnover number and a turnover frequency.

In one embodiment, the molar yield of the palladium cross-couplingproduct or derivatives thereof is at least 75% relative to the initialmolar amount of the aryl halide.

In one embodiment, the molar ratio of the aryl halide to the catalystcomposition is greater than 100.

In one embodiment, the palladium cross-coupling product or derivativesthereof comprises less than 100 ppb palladium, based on the total weightof the palladium cross-coupling product or derivatives thereof.

In one embodiment, the catalyst composition is reused in at least 2reaction cycles with a less than 20 percentage point decrease in a molaryield of the palladium cross-coupling product or derivatives thereofrelative to an initial molar amount of the aryl halide

The foregoing paragraphs have been provided by way of generalintroduction, and are not intended to limit the scope of the followingclaims. The described embodiments, together with further advantages,will be best understood by reference to the following detaileddescription taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the disclosure and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 is a chemical reaction scheme for the synthesis of thesolid-supported catalyst ligand wherein R₁ is —CH₃, R₂ is —CH₃, R₃ is—H, R₄ is —H, R₅ is —H, R₆ is —H, and X is O, and the solid support, SS,is Merrifield resin (BOX-3) starting from 4-iodophthalonitrile and2-amino-2-methyl-1-propanol.

FIG. 2 is chemical reaction scheme for the synthesis of the catalystcomposition wherein R₁ is —CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is—H, R₆ is —H, and X is O, the solid support, SS, is Merrifield resin,and the Pd⁺² species having the formula PdZ₂ is PdCl₂ (Pd-BOX) from thesolid-supported catalyst ligand wherein R₁ is —CH₃, R₂ is —CH₃, R₃ is—H, R₄ is —H, R₅ is —H, R₆ is —H, and X is O, and the solid support, SS,is Merrifield resin (BOX-3).

FIG. 3 is a scanning electron microscopy (SEM) image of a single bead ofpure unfunctionalized Merrifield resin.

FIG. 4 is a SEM image of the solid-supported catalyst ligand wherein R₁is —CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is —H, R₆ is —H, and X is O,and the solid support, SS, is Merrifield resin (BOX-3).

FIG. 5 is a SEM image of the catalyst composition wherein R₁ is —CH₃, R₂is —CH₃, R₃ is —H, R₄ is —H, R₅ is —H, R₆ is —H, and X is O, the solidsupport, SS, is Merrifield resin, and the Pd⁺² species having theformula PdZ₂ is PdCl₂ (Pd-BOX).

FIG. 6 is a chemical reaction scheme for the reaction of iodobenzenewith p-tolylboronic acid in the palladium cross-coupling Suzuki-Miyaurareaction.

FIG. 7 is a graph illustrating the isolated yields and recycling abilityof the palladium cross-coupling Suzuki-Miyaura reaction of iodobenzenewith p-tolylboronic acid in the presence of the catalyst compositionwherein R₁ is —CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is —H, R₆ is —H,and X is O, the solid support, SS, is Merrifield resin, and the Pd⁺²species having the formula PdZ₂ is PdCl₂ (Pd-BOX) with 0.0050 mmol [Pd],1.5 mmol p-tolylboronic acid, 1.0 mmol iodobenzene, and 2.0 mmol K₂CO₃in 3.0 mL DMF and 3.0 mL H₂O at 80° C. for 2 hours.

FIG. 8 is a chemical reaction scheme for the reaction of iodobenzenewith styrene in the palladium cross-coupling Mizoroki-Heck reaction.

FIG. 9 is a graph illustrating the isolated yields and recycling abilityof the palladium cross-coupling Mizoroki-Heck reaction of iodobenzenewith styrene in the presence of the catalyst composition wherein R₁ is—CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is —H, R₆ is —H, and X is O,the solid support, SS, is Merrifield resin, and the Pd⁺² species havingthe formula PdZ₂ is PdCl₂ (Pd-BOX) with 0.0050 mmol [Pd], 1.5 mmolstyrene, 1.0 mmol iodobenzene, and 2.0 mmol KOH in 3.0 mL DMF and 3.0 mLH₂O at 80° C. for 6 hours.

FIG. 10 is a chemical reaction scheme for the reaction of iodobenzenewith phenylacetylene in the palladium cross-coupling Sonagashirareaction.

FIG. 11 is a graph illustrating the isolated yields and recyclingability of the palladium cross-coupling Sonogashira reaction ofiodobenzene with phenylacetylene in the presence of the catalystcomposition wherein R₁ is —CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is—H, R₆ is —H, and X is O, the solid support, SS, is Merrifield resin,and the Pd⁺² species having the formula PdZ₂ is PdCl₂ (Pd-BOX) with0.0050 mmol [Pd], 1.5 mmol phenylacetylene, 1.0 mmol iodobenzene, and2.0 mmol KOH in 2.0 mL acetonitrile and 2.0 mL H₂O at 60° C. for 6hours.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Embodiments of the present disclosure will now be described more fullyhereinafter with reference to the accompanying drawings, in which some,but not all of the embodiments of the present disclosure are shown.

The present disclosure will be better understood with reference to thefollowing definitions.

As used herein, the words “a” and “an” and the like carry the meaning of“one or more”.

As used herein, the terms “compound”, “composition”, “complex” and“catalyst” are used interchangeably, and are intended to refer to achemical entity, whether in the solid, liquid or gaseous phase, as wellas in a crude mixture or in a purified and isolated form. The chemicaltransformations and/or reactions described herein are envisaged toproceed via standard laboratory and experimental techniques in regard toperforming the reaction as well as standard purification, isolation andcharacterization protocols known to those of ordinary skill in the art.

As used herein, the term “salt” refers to derivatives of the disclosedcompounds wherein the parent compound is modified by making acid or basesalts thereof. Exemplary salts include, but are not limited to, mineralor organic acid salts of basic groups such as amines, and alkali ororganic salts of acidic groups such as carboxylic acids. The saltsinclude, but are not limited to, the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. Exemplary conventionalnon-toxic salts include those derived from inorganic acids including,but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, and nitric; and those derived from organic acids including,but not limited to, acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and mixtures thereof and the like.Further, salts of carboxylic acid containing compounds may includecations such as lithium, sodium, potassium, magnesium, and the like. Thesalts of the present disclosure can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods. Generally such salts can be prepared by reacting the free acidor base forms of these compounds with a stoichiometric amount of theappropriate base or acid in water or in an organic solvent, or in amixture of the two; generally non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred.

As used herein, the term “solvate” refers to a physical association of acompound of this disclosure with one or more solvent molecules, whetherorganic or inorganic. This physical association includes hydrogenbonding. In certain instances, the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. The solvent molecules in thesolvate may be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. Solvate encompassesboth solution phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates ethanolates, methanolates,isopropanolates and mixtures thereof. Methods of solvation are generallyknown to those of ordinary skill in the art.

As used herein, the term “tautomer” refers to constitutional isomers oforganic compounds that readily convert by the chemical reaction oftautomerization or tautomerism. The reaction commonly results in theformal migration of a hydrogen atom or proton, accompanied by a switchof a single bond and adjacent double bond. Tautomerism is a special caseof structural isomerism and because of the rapid interconversion;tautormers are generally considered to be the same chemical compound. Insolutions in which tautomerization is possible, a chemical equilibriumof the tautomers will be reached. The exact ratio of the tautomersdepends on several factors including, but not limited to, temperature,solvent and pH. Exemplary common tautomeric pairs include, but are notlimited to, ketone and enol, enamine and imine, ketene and ynol, nitrosoand oxime, amide and imidic acid, lactam and lactim (an amide and imidictautomerism in heterocyclic rings), enamine and enamine and anomers ofreducing sugars.

Prototropy or prototropic tautomerism refers to the relocation of aproton. Prototropy may be considered a subset of acid base behavior.Prototropic tautomers are sets of isomeric protonation states with thesame empirical formula and total charge. Tautomerizations may becatalyzed by bases (deprotonation, formation of an enolate ordelocalized anion, and protonation at a different position of the anion)and/or acids (protonation, formation of a delocalized cation anddeprotonation at a different position adjacent to the cation). Twoadditional subcategories of tautomerization include annular tautomerism,wherein a proton can occupy two or more positions of a heterocyclicsystem, and ring-chain tautomerism, wherein the movement of a proton isaccompanied by a change from an open structure to a ring. Valencetautomerism is a type of tautomerism in which single and/or double bondsare rapidly formed and ruptured, without migration of atoms or groups.It is distinct from prototropic tautomerism, and involves processes withrapid reorganization of bonding electrons, such as open and closed formsof certain heterocycles, such as azide-tetrazole or mesoionicmunchnone-acylamino ketene. Valence tautomerism requires a change inmolecular geometry unlike canonical resonance structures or mesomers. Interms of the present disclosure, the tautomerism may refer toprototropic tautomerism, annular tautomerism, ring-chain tautomerism,valence tautomerism or mixtures thereof.

As used herein, the term “stereoisomer” refers to isomeric moleculesthat have the same molecular formula and sequence of bonded atoms (i.e.constitution), but differ in the three-dimensional orientations of theiratoms in space. This contrasts with structural isomers, which share thesame molecular formula, but the bond connection of their order differs.By definition, molecules that are stereoisomers of each other representthe same structural isomer. Enantiomers are two stereoisomers that arerelated to each other by reflection, they are non-superimposable mirrorimages. Every stereogenic center in one has the opposite configurationin the other. Two compounds that are enantiomers of each other have thesame physical properties, except for the direction in which they rotatepolarized light and how they interact with different optical isomers ofother compounds. Diastereomers are stereoisomers not related through areflection operation, they are not mirror images of each other. Theseinclude meso compounds, cis- and trans- (E- and Z-) isomers, andnon-enantiomeric optical isomers. Diastereomers seldom have the samephysical properties. In terms of the present disclosure, stereoisomersmay refer to enantiomers, diastereomers or both.

Conformers (rotamers), or conformational isomerism refers to a form ofisomerism that describes the phenomenon of molecules with the samestructural formula but with different shapes due to rotations about oneor more bonds. Different conformations can have different energies, canusually interconvert, and are very rarely isolatable. There are somemolecules that can be isolated in several conformations. Atropisomersare stereoisomers resulting from hindered rotation about single bondswhere the steric strain barrier to rotation is high enough to allow forthe isolation of the conformers. In terms of the present disclosure,stereoisomers may refer to conformers, atropisomers, or both.

In terms of the present disclosure, stereoisomers of the double bonds,ring systems, stereogenic centers, and the like can all be present inthe compounds, and all such stable isomers are contemplated in thepresent disclosure. Cis- and trans- (or E- and Z-) stereoisomers of thecompounds of the present disclosure wherein rotation about the doublebond is restricted, keeping the substituents fixed relative to eachother, are described and may be isolated as a mixture of isomers or asseparated isomeric forms. S- and R- (or L- and D-) stereoisomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. All processes ormethods used to prepare compounds of the present disclosure andintermediates made therein are considered to be part of the presentdisclosure. When stereoisomeric products are prepared, they may beseparated by conventional methods, for example by chromatography,fractional crystallization, or use of a chiral agent.

As used herein, the term “substituted” refers to at least one hydrogenatom that is replaced with a non-hydrogen group, provided that normalvalencies are maintained and that the substitution results in a stablecompound. When a compound or substituent (—R group denoted as R₁, R₂, R₃and so forth) is noted as “optionally substituted”, the substituents areselected from the exemplary group including, but not limited to, halo,hydroxyl, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino,alkylamino, arylamino, arylalkylamino, disubstituted amines (e.g. inwhich the two amino substituents are selected from the exemplary groupincluding, but not limited to, alkyl, aryl or arylalkyl), alkanylamino,aroylamino, aralkanoylamino, substituted alkanoylamino, substitutedarylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio,arylalkylthio, alkylthiono, arylthiono, aryalkylthiono, alkylsulfonyl,arylsulfonyl, arylalkylsulfonyl, sulfonamide (e.g.—SO₂NH₂), substitutedsulfonamidc, nitro, cyano, carboxy, carbamyl (e.g.—CONH₂), substitutedcarbamyl (e.g.—CONHalkyl, —CONHaryl, —CONHarylalkyl or cases where thereare two substituents on one nitrogen from alkyl, aryl, or alkylalkyl),alkoxycarbonyl, aryl, substituted aryl, guanidine, heterocyclyl (e.g.indolyl, imidazoyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,pyrimidiyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,homopiperazinyl and the like), substituted heterocyclyl and mixturesthereof and the like. The substituted moiety may be either protected orunprotected as necessary, and as known to those skilled in the art.

As used herein, the term “alkyl” unless otherwise specified refers toboth branched and straight chain saturated aliphatic primary, secondary,and/or tertiary hydrocarbons or hydrocarbon fragments of typically C₁ toC₁₀, and specifically includes, but is not limited to, methyl,trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl,t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl,cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and2,3-dimethylbutyl. As used herein, the term optionally includessubstituted alkyl groups. Exemplary moieties with which the alkyl groupcan be substituted may be selected from the group including, but notlimited to, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy,nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, orphosphonate or mixtures thereof. The substituted moiety may be eitherprotected or unprotected as necessary, and as known to those skilled inthe art.

As used herein, the term “cycloalkyl” refers to cyclized alkyl groups.Exemplary cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, andadamantyl. Branched cycloalkyl groups such as exemplary1-methylcyclopropyl and 2-methylcyclopropyl groups are included in thedefinition of cycloalkyl as used in the present disclosure.

As used herein, the term “aryl” unless otherwise specified refers tofunctional groups or substituents derived from an aromatic ringincluding, but not limited to, phenyl, biphenyl, napthyl, thienyl, andindolyl. As used herein, the term optionally includes both substitutedand unsubstituted moieties. Exemplary moieties with which the aryl groupcan be substituted may be selected from the group including, but notlimited to, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy,nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate orphosphonate or mixtures thereof. The substituted moiety may be eitherprotected or unprotected as necessary, and as known to those skilled inthe art.

As used herein, the term “heterocyclyl” unless otherwise specifiedrefers to a 3-8, preferably 4-8, more preferably 4-7 membered monocyclicring or a fused 8-12 membered bicyclic ring which may be saturated orpartially unsaturated, which monocyclic or bicyclic ring contains 1 to 4heteroatoms selected from oxygen, nitrogen, silicon or sulfur. Examplesof such monocyclic rings include oxaziridinyl, homopiperazinyl,oxiranyl, dioxiranyl, aziridinyl, pyrrolidinyl, azetidinyl,pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl,oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl,dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl,tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, diazepanyl and azepanyl. Examples of suchbicyclic rings include indolinyl, isoindolinyl, benzopyranyl,quinuclidinyl, 2,3,4,5-tetrahydro-1,3,benzazepine,4-(benzo-1,3,dioxol-5-methyl)piperazine, and tetrahydroisoquinolinyl.Further, “substituted heterocyclyl” may refer to a heterocyclyl ringwhich has one or more oxygen atoms bonded to the ring (i.e. as ringatoms). Preferably, said atom which is bonded to the ring selected fromnitrogen or sulphur. An example of a heterocyclyl substituted with oneor more oxygen atoms is 1,1-dioxido-1,3-thiazolidinyl.

As used herein, “alkylthio” refers to a divalent sulfur with alkyloccupying one of the valencies and includes the groups methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio, octylthio. Asused herein, “alkanoyl” as used in this disclosure refers to an alkylgroup having 2 to 18 carbon atoms that is bound with a double bond to anoxygen atom. Examples of alkanoyl includes, acetyl, propionyl, butyryl,isobutyryl, pivaloyl, valeryl, hexanoyl, octanoyl, lauroyl, stearoyl. Asused herein, “arylalkyl” refers to a straight or branched chain alkylmoiety having 1 to 8 carbon atoms that is substituted by an aryl groupor a substituted aryl group having 6 to 12 carbon atoms, and includesbenzyl, 2-phenethyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,2,4-dimethylbenzyl, 2-(4-ethylphenyl)ethyl, 3-(3-propylphenyl)propyl.Examples of aroyl are benzoyl and naphthoyl, and “substituted aroyl” mayrefer to benzoyl or naphthoyl substituted by at least one substituentincluding those selected from halogen, amino, vitro, hydroxy, alkyl,alkoxy and haloalkyl on the benzene or naphthalene ring.

As used herein, “heteroarylcarbonyl” refers to a heteroaryl moiety with5 to 10 membered mono- or fused-heteroaromatic ring having at least oneheteroatom selected from nitrogen, oxygen and sulfur as mentioned above,and includes, for example, furoyl, nicotinoyl, isonicotinoyl,pyrazolylcarbonyl, imidazolylcarbonyl, pyrimidinylcarbonyl,benzimidazolyl-carbonyl. Further, “substituted heteroarylcarbonyl” mayrefer to the above mentioned heteroarylcarbonyl which is substituted byat least one substituent selected from halogen, amino, vitro, hydroxy,alkoxy and haloalkyl on the heteroaryl nucleus, and includes, forexample, 2-oxo-1,3-dioxolan-4-ylmethyl, 2-oxo-1,3-dioxan-5-yl. As usedherein, vinyl refers to an unsaturated substituent having at least oneunsaturated double bond and having the formula CH₂═CH—. Accordingly,said “substituted vinyl” may refer to the above vinyl substituent havingat least one of the protons on the terminal carbon atom replaced withalkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, heteroarylor substituted heteroaryl.

As used herein, “hydrocarbyl” refers to a univalent hydrocarbon groupcontaining up to about 24 carbon atoms (i.e., a group containing onlycarbon and hydrogen atoms) and that is devoid of olefinic and acetylenicunsaturation, and includes alkyl, cycloalkyl, alkyl-substitutedcycloalkyl, cycloalkyl-substituted cycloalkyl, cycloalkylalkyl, aryl,alkyl-substituted aryl, cycloalkyl-substituted aryl, arylalkyl,alkyl-substituted aralkyl, and cycloalkyl-substituted aralkyl. Further,functionally-substituted hydrocarbyl groups may refer to a hydrocarbylgroup that is substituted by one or more functional groups selected fromhalogen atoms, amino, nitro, hydroxy, hydrocarbyloxy (including alkoxy,cycloalkyloxy, and aryloxy), hydrocarbylthio (including alkylthio,cycloalkylthio, and arylthio), heteroaryl, substituted heteroaryl,alkanoyl, aroyl, substituted aroyl, heteroarylcarbonyl, and substitutedheteroarylcarbonyl.

As used herein, the term “solvent” refers to and includes, but is notlimited to, water (e.g. tap water, distilled water, deionized water,deionized distilled water), organic solvents, such as ethers (e.g.diethyl ether, tetrahydrofuran, 1,4-dioxane, tetrahydropyran, t-butylmethyl ether, cyclopentyl methyl ether, di-iso-propyl ether), glycolethers (e.g. 1,2-dimethoxyethane, diglyme, triglyme), alcohols (e.g.methanol, ethanol, trifluoroethanol, n-propanol, i-propanol, n-butanol,i-butanol, t-butanol, n-pentanol, i-pentanol, 2-methyl-2-butanol,2-trifluoromethyl-2-propanol, 2,3-dimethyl-2-butanol, 3-pentanol,3-methyl-3-pentanol, 2-methyl-3-pentanol, 2-methyl-2-pentanol,2,3-dimethyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-hexanol,3-hexanol, cyclopropylmethanol, cyclopropanol, cyclobutanol,cyclopentanol, cyclohexanol), aromatic solvents (e.g. benzene, o-xylene,m-xylene, p-xylene, and mixtures of xylenes, toluene, mesitylene,anisole, 1,2-dimethoxybenzene, α,α,α,-trifluoromethylbenzene,fluorobenzene), chlorinated solvents (e.g. chlorobenzene,dichloromethane, 1,2-dichloroethane, 1,1-dichlorocthane, chloroform),ester solvents (e.g. ethyl acetate, propyl acetate), amide solvents(e.g. dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone),urea solvents, ketones (e.g. acetone, butanone), acetonitrile,propionitrile, butyronitrile, benzonitrile, dimethyl sulfoxide, ethylenecarbonate, propylene carbonate,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, and mixturesthereof. As used herein solvent may refer to non-polar solvents (e.g.hexane, benzene, toluene, diethyl ether, chloroform, 1,4-dioxane), polaraprotic solvents (e.g. ethyl acetate, tetrahydrofuran, dichloromethane,acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide) and polarprotic solvents (e.g. acetic acid, n-butanol, isopropanol, n-propanol,ethanol, methanol, formic acid, water) and mixtures thereof.

As used herein, the term “base” refers to and includes, but is notlimited to, an alkali metal hydride (e.g. sodium hydride, potassiumhydride), an alkali metal hydroxide (e.g. lithium hydroxide, potassiumhydroxide, sodium hydroxide, cesium hydroxide), an alkali metalcarbonate (e.g. lithium carbonate, potassium carbonate, sodiumcarbonate, cesium carbonate), an alkali metal acetate (e.g. lithiumacetate, sodium acetate, potassium acetate), an amine (e.g. atrialkylamine of formula NR′₃, wherein each R′ may be independentlyethyl, n-propyl, and n-butyl, a dialkylamine of formula HNR′₂,diethylamine, di-n-butylamine, pyrrolidine, piperidine, triethylamine,tri-n-butylamine, diisopropylethylamine, dicyclohexylmethylamine,pyridine, 2,6-dimethylpyridine, 4-aminopyridine,N-methyl-2,2,6,6-tetramethylpiperidine, 2,2,6,6-tetramethylpiperidine,2,6-di-tert-butylpyridine, 1,4-diazabicyclo[2.2.2]octane, and mixturesthereof), and mixtures thereof. The presence of a base is oftenimportant for the palladium-catalyzed cross-coupling reactions in orderto neutralize any hydrogen halide produced as a byproduct of thecoupling reaction

As used herein, the term “derivative” refers to a chemically modifiedversion of a chemical compound that is structurally similar to a parentcompound.

The present disclosure is further intended to include all isotopes ofatoms occurring in the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example, and without limitation, isotopes of hydrogen includedeuterium and tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes and methods analogous to those described herein, using anappropriate isotopically labeled reagent in place of the non-labeledreagent otherwise employed.

According to a first aspect, the present disclosure relates to a solidsupported catalyst ligand of formula (I)

or a salt, solvate, tautomer or stereoisomer thereof wherein i) R₁, R₂,R₃ and R₄ are independently —H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, or an optionally substituted aryl,ii) each R₅ and R₆ is independently —H, an optionally substituted alkyl,an optionally substituted cycloalkyl, or an optionally substituted aryl,iii) X is O, NH, or S, and iv) SS is a solid support with the provisothat the solid support is not silica. In a preferred embodiment, thesolid support is Merrifield resin.

Substituents R₁, R₂, R₃ and R₄ are independently —H, an optionallysubstituted alkyl, an optionally substituted cycloalkyl, or anoptionally substituted aryl, preferably R₁ is —CH₃, R₂ is —CH₃, R₃ is—H, R₄ is —H and X is O. In certain embodiments, substituents R₁, R₂, R₃and R₄ may be independently an optionally substituted cycloalkylalkyl,an optionally substituted arylalkyl, an optionally substitutedheteroaryl, an optionally substituted heterocyclyl, an optionallysubstituted alkylthio, an optionally substituted alkanoyl, an optionallysubstituted aroyl, an optionally substituted heteroarylcarbonyl, anoptionally substituted hydrocarbyl, an optionally substitutedarylolefin, an optionally substituted arylalkylcarboxylic acid, or anoptionally substituted vinyl.

Each R₅ and R₆ is independently —H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, or an optionally substituted aryl,preferably R₅ is —H, R₆ is —H, and X is O. In certain embodiments, eachR₅ and R₆ substituent may be independently an optionally substitutedcycloalkylalkyl, an optionally substituted arylalkyl, an optionallysubstituted heteroaryl, an optionally substituted heterocyclyl, anoptionally substituted alkylthio, an optionally substituted alkanoyl, anoptionally substituted aroyl, an optionally substitutedheteroarylcarbonyl, an optionally substituted hydrocarbyl, an optionallysubstituted arylolefin, an optionally substituted arylalkylcarboxylicacid, or an optionally substituted vinyl.

The optionally substituted alkyl group may comprise 1-8 carbon atoms,preferably 1-5 carbon atoms, more preferably 1-3 carbon atoms. In oneembodiment, the optionally substituted alkyl group comprises 1 carbonatom and is a methyl group. The optionally substituted aryl group ispreferably a phenyl group. The alkyl and aryl groups may be substitutedwith the aforementioned substituents. Preferably, the alkyl and/or thearyl groups are substituted with hydroxyl, alkoxy, aryloxy, nitro, orcyano, either unprotected, or protected as necessary.

In certain embodiments, R₁, R₂, R₃, R₄, R₅, R₆, and R₇ may beindependently a halogen atom, a hydroxyl, a nitro, a cyano, anoptionally substituted heterocyclyl, an optionally substitutedarylalkyl, an optionally substituted heteroaryl, or an optionallysubstituted alkoxyl. The optionally substituted heterocyclyl may be aderivative of an O-heterocyclyl such as tetrahydrofuran,tetrahydropyran, or dioxane. The optionally substituted heteroaryl maybe a derivative of an O-heteroaromatic compound such as furan. Theoptionally substituted arylalkyl may be, but is not limited to, benzyl,phenethyl, and phenylpropyl. The optionally substituted alkoxyl may be,but is not limited to, methoxy, ethoxy, and phenoxyl.

In certain embodiments, R₁ and R₂ may not be an amino, an alkylamino, anarylamino, a N-monosubstituted amino, a N,N-disubstituted amino, a thiolor an optionally substituted thioalkoxyl because these groups containnucleophilic atoms that may poison the catalyst. As used herein, theterm “poisoning” refers to the nucleophilic atom(s) coordinatingstrongly to the palladium ion and thereby reducing the effectiveness ofthe catalyst.

As used herein, a solid support or catalyst support is a material,usually a solid with a high surface area, to which a catalyst orcatalyst ligand is affixed. The activity of heterogeneous catalyst andnanomaterial-based catalysts occurs at the surface atoms.

Consequently, great effort is made to maximize the surface area of acatalyst by distributing it over the support. The solid support may beinert or participate in the catalytic reactions, preferably it is inert.The recycling of homogeneous catalyst is complex and costly.

Therefore, the use of immobilized catalyst is an alternative forindustries to combine the advantages of both homogeneous andheterogeneous catalyst and also to overcome the problems related tometal contamination.

In certain embodiments, the solid support may be functionalized tofacilitate a covalent attachment of the ligand. As used herein, the term“functionalize” refers to the modification of a surface of the solidsupport particle with an organic moiety containing carbon. Exemplaryorganic moieties include, without limitation, 4-benzyl chloride,3-aminopropyl, 4-bromopropyl, 4-bromophenyl, 3-carboxypropyl,2-(carbomethoxy)propyl, 3-chloropropyl, 3-(2-succinic anhydride)propyl,1-(allyl)methyl, 3-(thiocyano)propyl, 3-(isocyano)propyl, propionylchloride, 3-(maleimido)propyl, 3-(glycidoxy)propyl, 4-ethylbenzenesulfonyl chloride, 2-(3,4-epoxycyclohexyl)propyl, and3-propylsulfonic acid, preferably 4-benzyl chloride. A loading of theorganic moiety on the solid support may be in a range of 0.5-20 mmol/g,preferably 1-10 mmol/g, preferably 1-5 mmol/g, more preferably 1-3mmol/g

The nature of the solid support is not envisioned as particularlylimiting. In certain embodiments, the catalyst is preferably immobilizedby covalent coupling to a grafted or a functionalized polystyrenesupport. Exemplary functionalized polystyrene supports include, but arenot limited to Wang resin, Argogel resin, Merrifield resin, Tentagelresin, Polyaamine resins, and the like, preferably Merrifield resin. Incertain embodiments, the catalyst may be immobilized by covalentcoupling to a grafted or a functionalized polymer support, wherein thefunctionalized polymer support is at least one selected from the groupconsisting of polyolefins, polyacrylates, polymethacrylates, andcopolymers thereof.

In a most preferred embodiment, the solid support is Merrifield resin.As used herein, Merrifield resin refers to a cross-linked polystyreneresin that carries a chloromethyl functional group. Merrifield resin maybe thought of as a polystyrene resin based on a copolymer of styrene andchloromethyl styrene. This polymer may further be cross-linked withdivinyl benzene, wherein a degree of crosslinking is within the range of1-5%, preferably 1-2%. In certain embodiments, the solid supportcomprises at least 10 wt % Merrifield resin relative to the total weightof the solid support, preferably at least 50 wt %, preferably at least70 wt %, preferably at least 80 wt %, preferably at least 90 wt %,preferably at least 95 wt %, preferably at least 96 wt %, preferably atleast 97 wt %, preferably at least 98 wt %, preferably at least 99 wt %Merrifield resin relative to the total weight of the solid support. Itis equally envisioned that one or more solid supports may be used inaddition to, or in lieu of Merrifield resin.

Alternatively, in certain embodiments, the catalyst may be immobilizedby covalent coupling such as through a silicon or siloxane containinglinker to a porous or nonporous solid support. Exemplary possiblesupports include, but are not limited to, alumina, titanium, kieselguhr,diatomaceous earth, clay, zeolites, carbon black, activated carbon,graphite, fluorinated carbon, organic polymers, metals, metal alloys,and mixtures thereof.

All embodiments carry the proviso that the solid support is not silica,particularly silica gel. As used herein “not silica” describes that thesolid support comprises less than 25 wt % relative to the total weightof the solid support of a silica solid support, preferably less than 20wt %, preferably less than 15 wt %, preferably less than 10 wt %,preferably less than 5 wt %, preferably less than 4 wt %, preferablyless than 3 wt %, preferably less than 2 wt %, preferably less than 1 wt%, preferably less than 0.1 wt % based on the total weight of the solidsupport of a silica solid support. Exemplary silica solid supportsinclude, but are not limited to, zeolite/aluminum silicate (e.g.andalusite, kyanite, sillimanite, kaolinite, metakalonite, 3:2 mullite,2:1 mullite), amorphous silica, crystalline silica, fibrous silica,precipitated silica, mesoporous silica (e.g. MCM-41 and SBA-15), fumedsilica, silica alumina, and silica gel, particularly silica gel.

The solid support, the solid-supported catalyst ligand or both may be ina form of a particle with a shape of a sphere, ellipsoid, cube, cuboid,cylindrical, or polygonal prism (e.g. triangular prism, hexagonal prism,and pentagonal prism). In a preferred embodiment, the solid supportand/or solid-supported catalyst ligand particle has an irregular shape.An average diameter of the solid support and/or solid-supported catalystligand particle may be in a range of 1-100 μm, preferably 20-80 μm, morepreferably 35-75 μm. In other embodiments, the average diameter of thesolid support and/or solid-supported catalyst ligand particle is in arange of 0.5-1000 nm, preferably 1-500 nm, more preferably 5-100 nm. Forspherical, ellipsoidal, or irregularly-shaped particles, the term“diameter” refers to a longest straight-line distance between two pointson a surface of the particle.

In a preferred embodiment, a surface area of the solid support particle,the solid-supported catalyst ligand or both may range from 100-2000m²/g, preferably 300-1000 m²/g, more preferably 500-1000 m²/g. Incertain embodiments, the solid support particle may comprise pores withan average diameter in a range of 0.5-50 nm, preferably 0.5-30 nm, morepreferably 0.5-10 nm. In certain embodiments, a porosity of the solidsupport may be in a range of 1-99%, preferably 20-90%, more preferably40-80%. In one embodiment, the solid support is non-porous. In apreferred embodiment, the catalyst ligand covers greater than 50% of thesurface area of the solid support, preferably greater than 60%,preferably greater than 70%, preferably greater than 80%, preferablygreater than 85%, preferably greater than 90%, preferably greater than95% of the surface area of the solid support. In a preferred embodiment,the solid support is Merrifield resins and greater than 25% of theavailable chloromethyl substituents are bound to the catalyst ligand,preferably greater than 50%, preferably greater than 60%, preferablygreater than 70%, preferably greater than 80%, preferably greater than85%, preferably greater than 90%, preferably greater than 95% of theavailable chloromethyl substituents are bound to the catalyst ligand.

In a preferred embodiment, R₁ is —CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H,R₅ is —H, R₆ is —H, and X is O and the solid-supported catalyst ligandof formula (I) is

or a salt, solvate, tautomer or stereoisomer thereof wherein SS is asolid support with the proviso that the solid support, preferablyMerrifield resin, is not silica. In a most preferred embodiment, R₁ is—CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is —H, R₆ is —H, and X is O,the solid-supported catalyst ligand of formula (I) is the compound BOX-3as above and the solid support is Merrifield resin.

According to a second aspect, the present disclosure relates to acatalyst composition or solid-supported catalyst, comprising i) thesolid-supported catalyst ligand of the first aspect and ii) a catalyticmetal in the form of a Pd²⁺ species or salt having the formula PdZ₂,wherein the nitrogen atoms of the two oxazoline heterocycles bind orchelate the catalytic palladium (II) metal and wherein Z is selectedfrom the group consisting of —Cl, —I, —Br, —OAc, and —Otf. The terms“catalyst composition”, “solid-supported palladium (II) complex” or“solid-supported catalyst” are used interchangeably. In a preferredembodiment, the catalyst composition or solid-supported catalyst isrepresented by a compound of formula (II)

or a salt, solvate, tautomer or stereoisomer thereof, wherein R₁, R₂, R₃and R₄ are independently —H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, or an optionally substituted aryl,each R₅ and R₆ is independently —H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, or an optionally substituted aryl, Xis O, NH, or S, and SS is a solid support with the proviso that thesolid support is not silica. In a most preferred embodiment, the solidsupport is Merrifield resin.

As used herein, a ligand refers to in coordination chemistry an ion ormolecule (functional group) that binds a central metal atom to form acoordination complex. The binding between metal and ligand generallyinvolves formal donation of one or more of the ligand's electron pairs.The nature of the metal-ligand bonding can range from covalent to ionicand the metal-ligand bond order can range from one to three. Ligands areclassified in many ways including, but not limited to, size (bulk), theidentity of the coordinating atom(s), and the number of electronsdonated to the metal (i.e. denticity or hapticity). Denticity refers tothe number of times a ligand bonds to a metal through noncontiguousdonor sites. Many ligands are capable of binding metal ions throughmultiple sites, usually because the ligands have lone pairs on more thanone atom. A ligand that binds through one site is classified asmonodentate, a ligand that binds through two sites is classified asbidentate, three sites as tridentate and more than one site aspolydentate. Ligands that bind via more than one atom are often termedchelating. Complexes of polydentate ligands are called chelatecomplexes. As used herein, chelation is a particular type of way ionsand molecules bind to metal ions. It involves the formation or presenceof two or more coordinate bonds between a polydentate (multiple bonded)ligand and a single central atom. These ligands are often organiccompounds and may be referred to as chelants, chelators, chelatingagents, or sequestering agents. The chelate effect describes theenhanced affinity of chelating ligands for a metal ion compared to theaffinity of a collection of similar non-chelating (i.e. monodentate)ligands for the same metal. In terms of the present disclosure, thesolid-supported catalyst ligand of the present disclosure may bind withone or more catalytic metal ions by monodentate coordination, orpolydentate chelation including, but not limited to bidentate chelationor tridentate chelation to the metal ion, preferably Pd (II).

Herein, a ligand specifically may refer to an organic moleculecomprising at least a phenyl ring and two oxazoline groups boundseparately to the phenyl ring via a C—C bond and arranged ortho to oneanother, wherein each oxazoline group comprises a nitrogen atom whichcan bind to the palladium (II) ion covalently thereby forming a chelate.In a preferred embodiment, the nitrogen atoms of the two oxazolineheterocycles chelate the catalytic metal in a bidentate manner and thecatalyst composition or solid-supported catalyst has a distorted squareplane or square planar geometry. As used herein, square planar moleculargeometry describes the stereochemistry (spatial arrangement) of atomsthat is adopted by certain chemical compounds wherein molecules of thisgeometry have their atoms (i.e. oxazoline —N) positioned at the cornersof a square on the same plane about a central atom (i.e. Pd²⁺).

As used herein, the term catalytic metal in the form of a Pd⁺² speciesor palladium (II) salt having the formula PdZ₂ includes, but is notlimited to, palladium (II) chloride, palladium (II) bromide, palladium(II) iodide, bis(benzonitrile) palladium (II) chloride,bis(acetonitrile) palldium (II) chloride, palladium (II) acetate,palladium (II) triflate, and the like. It is equally envisioned that thesolid supported catalytic ligand of the present disclosure may beadapted to or in its present form bind one or more additional catalyticmetals. Exemplary additional catalytic metals that may be bound inaddition to or in lieu of Pd (II) include, but are not limited tonickel, platinum, rhodium, iron, gold, silver, ruthenium, and iridium.

In a preferred embodiment, R₁ is —CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H,R₅ is —H, R₆ is —H, and X is O, and the Pd¹² species having the formulaPdZ₂ is PdCl₂ and the catalyst composition or solid-supported catalystaccording to formula (II) is

or a salt, solvate, tautomer or stereoisomer thereof wherein SS is asolid support with the proviso that the solid support, preferablyMerrifield resin, is not silica. In a most preferred embodiment, R₁ is—CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is —H, R₆ is —H, and X is O,the solid-supported catalyst ligand of formula (I) is the compoundPd-BOX as above and the solid support is Merrifield resin.

In a preferred embodiment, the solid-supported catalyst or catalystcomposition comprises 0.05-1.5 mmol of palladium per gram ofsolid-supported catalyst, preferably 0.1-1.0 mmol/g, preferably 0.2-0.9mmol/g, preferably 0.3-0.8 mmol/g, preferably 0.4-0.7 mmol/g, preferably0.45-0.65 mmol/g, preferably 0.5-0.6 mmol of palladium per gram ofsolid-supported catalyst. In certain embodiments, the amount ofpalladium loading in the solid-supported catalyst or catalystcomposition may be determined by elemental analysis and/or inductivelycoupled plasma mass spectroscopy (ICP-MS). In a preferred embodiment,the solid-supported catalyst or catalyst composition has a turnovernumber in the range of 1500-2500, preferably 1500-2000, preferably1700-2000. In a preferred embodiment, the solid-supported catalyst orcatalyst composition has a turnover frequency in the range of 200-1500cycle per hour, preferably 200-1000 cycles per hour, more preferably200-500 cycles per hour. In certain embodiments, the aforementionedvalues of turnover number and turnover frequency of the solid-supportedcatalyst or catalyst composition may be observed when the catalystcatalyzes any palladium catalyzed reaction, preferably any palladiumcross-coupling reaction. Exemplary palladium cross-coupling reactionsinclude, but are not limited to, Mizoroki-Heck reaction,Mizoroki-Heck-Matsuda reaction, Sonagashira reaction, Kumada reaction,Negishi reaction, Stille reaction, Suzuki reaction, Suzuki-Miyaurareaction, Hiyama reaction, Buchwald-Hartwig reaction, and the like.

According to a third aspect, the present disclosure relates to a processfor producing the solid-supported catalyst ligand, comprising i)reacting a phthalonitrile compound with halogen substitution at the4-position (i.e. 4-halopthalonitrile) with a 2-aminoalcohol (i.e.β-amino alcohol) in the presence of a Lewis acid catalyst to form ahalogen substituted phenyl bisoxazoline ligand, ii) reacting the halogensubstituted phenyl bisoxazoline ligand with a para-substitutedphenylboronic acid compound in the presence of Pd²⁺ and a first base toform a functionalized diphenyl bisoxazoline ligand, and iii) reactingthe functionalized diphenyl bisoxazoline ligand with a second base inthe presence of the solid support to form the solid-supported catalystligand, wherein the para-substituted phenylboronic acid has apara-substituent that is a hydroxyl, a thiol, or an amino group.

In one step of the 4-halopthalonitrile compound is reacted with a2-aminoalcohol in the presence of a Lewis acid catalyst to form ahalogen substituted phenyl bisoxazoline ligand. In a preferredembodiment, the 4-halopthalonitrile compound is a compound of formula(III)

or a salt, solvate, tautomer or stereoisomer thereof, wherein each R₅ isindependently —H, an optionally substituted alkyl, an optionallysubstituted cycloalkyl, or an optionally substituted aryl and Y is —I,—Br, or —Cl, preferably each R₅ is —H and Y is —I. In a preferredembodiment the compound of formula (III) is

In a preferred embodiment, the 2-aminoalcohol is a compound of formula(IV)

or a salt, solvate, tautomer or stereoisomer thereof, wherein R₁, R₂,R₃, and R₄ are independently —H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, or an optionally substituted aryl,preferably R₁ and R₂ are —CH₃, and R₃ and R₄ are —H. In a preferredembodiment, the compound of formula (IV) is

As used herein, a Lewis acid catalyst or Lewis acid catalysis refers toorganic reactions wherein a metal-based Lewis acid acts as an electronpair acceptor to increase the reactivity of a substrate. Common Lewisacid catalyst are based on main group metals including, but not limitedto, aluminum, boron, silicon, and tin, as well as many early (i.e.titanium, zirconium) and late (i.e. iron, copper, zinc) d-block metals.Generally, the metal atom forms an adduct with a lone-pair bearingelectronegative atom in the substrate such as oxygen (both sp² or sp³),nitrogen, sulfur, and/or halogens. The complexation generally haspartial charge-transfer character and makes the lone-pair donoreffectively more electronegative, activating the substrate towardnucleophilic attack, heterocyclic bond cleavage, or cycloaddition. Manyreaction involving carbon-carbon or carbon-heteroatom bond formation canbe catalyzed by Lewis acids. Exemplary Lewis acid catalysts or reagentsinclude, but are not limited to, TiC₄, BF₃, SnCl₄, AlCl₃ and the like.In a preferred embodiment, the Lewis acid catalyst is a triflate ortriflate salt, preferably a transition metal triflate salt, mostpreferably zinc triflate (Zn(OTf)₂). In certain embodiments, othertriflate salts such as lanthanide triflates of the formula Ln(OTf)₃(where Ln=La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y) andscandium triflate are used.

In a preferred embodiment, the 4-halophthalonitrile, preferably4-iodophthalonitrile, and the Lewis acid catalyst, preferably a triflateor triflate salt, most preferably zinc triflate (Zn(OTf)₂) in a driedorganic solvent, preferably chlorobenzene are stirred at roomtemperature for approximately 15 minutes. An amount of4-halophthalonitrile in a range of 1-20 mmol, preferably 1-10 mmol, morepreferably 1-5 mmol and an amount of the Lewis acid triflate salt is ina range of 0.1-1 mmol, preferably 0.1-0.5 mmol, more preferably 0.1-0.3mmol, and 1-10 mol % relative to the number of moles of the4-halophthalonitrile, preferably 1-8 mol %, more preferably 3-6 mol %.Exemplary organic solvents include, but are not limited to, benzene,toluene, p-xylene, o-xylene, and m-xylene. An amount of the organicsolvent is in a range of 5-50 ml, preferably 10-40 ml, more preferably20-40 ml. The solution may be stirred for 5-60 minutes, preferably 5-30minutes, more preferably 10-20 minutes at a temperature in a range of10-40° C., preferably 15-30° C., more preferably 20-30° C.

A solution of the 2-aminoalcohol of β-amino alcohol of the followingstructure, preferably 2-amino-2-methyl-1-propanol in dried chlorobenzenemay be added to the solution of 4-halophthalonitrile and triflate saltin dried chlorobenzene to form a reaction mixture. An amount of theβ-amino alcohol is in a range of 1-40 mmol, preferably 1-30 mmol, morepreferably 1-15 mmol, and a molar ratio of 2-amino-1-propanol to4-halophthalonitrile is in a range of 1:1 to 20:1, preferably 1:1 to10:1, more preferably 1:1 to 5:1. The 2-aminoalcohol may be furthersubstituted and comprise the aforementioned substituents on C-1, C-2, orboth, and may be a chiral reagent, an achiral reagent, or a racemicmixture. Preferably, an achiral 2-amino-2-methyl-1-propanol is used. Inother embodiments, a chiral ligand is prepared by employing only one ofthe enantiomers of 2-amino-1-propanol (or further substituted2-amino-1-propanol), such as (S)-(+)-2-amino-1-propanol or(R)-(−)-2-amino-1-propanol.

The temperature of the reaction mixture may be raised to 80-160° C.,preferably 100-160° C., more preferably 110-140° C. and may be refluxedfor 12-48 hours, preferably 18-48 hours, more preferably 18-36 hours.The precursor, the halogen substituted phenyl bisoxazoline ligand, maybe isolated and purified by methods known to those skilled in the art,such as filtration through a celite containing cartridge, aqueouswork-up, extraction with organic solvents, distillation,crystallization, column chromatography, and high pressure liquidchromatography (HPLC) on normal phase or reversed phase. Preferredmethods include, extraction with organic solvents and columnchromatography, but are not limited to those exemplified. The yield ofthe precursor, the halogen substituted phenyl bisoxazoline ligand is atleast 50%, preferably at least 75%, more preferably at least 80%.

In another step, the precursor, halogen substituted phenyl bisoxazolineligand reacts with a para-substituted phenylboronic acid compound,arylboronic acid, or equally envisaged arylboronic ester in the presenceof Pd²⁺ and a first base to form a functionalized diphenyl bisoxazolineligand. In a preferred embodiment, the precursor, halogen substitutedphenyl bisoxazoline ligand is a compound of formula V

or a salt, solvate, tautomer or stereoisomer thereof, wherein each R₅ isindependently —H, an optionally substituted alkyl, an optionallysubstituted cycloalkyl, or an optionally substituted aryl and Y is —I,—Br, or —Cl, preferably each R₅ is —H and Y is —I. In a preferredembodiment the compound of formula (V) is

2,2′-(4-Iodobenzene-1,2-diyl)bis(4,4-dimethyl-4,5-dihydro-1,3-oxazole)or the bis(oxazoline) precursor ligand (BOX-1).

In a preferred embodiment, the para-substituted phenylboronic acid is acompound of formula (VI)

or a salt, solvate, tautomer or stereoisomer thereof, wherein each R₆ isindependently —H, an optionally substituted alkyl, an optionallysubstituted cycloalkyl, or an optionally substituted aryl and n is 1with the proviso that X is O or S or n is 2 with the proviso that X isN, preferably each R₆ is —H, n is 1, and X is O. In a preferredembodiment the compound of formula (VI) is

In a preferred embodiment, the precursor halogen substituted phenylbisoxazoline ligand, a palladium(II) salt or Pd⁺² source, a first base,and an arylboronic acid or an arylboronic ester, preferably anpara-substituted phenylboronic acid may be added to a solvent and heatedto a temperature in a range of 50-150° C., preferably 60-100° C., morepreferably 60-80° C. for 1-48 hours, preferably 1-24 hours, morepreferably 1-10 hours. Preferably, the palladium(II) salt or Pd⁺² sourceis palladium(II) chloride, the base is an alkali carbonate, preferablypotassium carbonate, and the solvent may comprise water, alcohol,toluene, dimethyl formamide, tetrahydrofuran, acetone, or mixturesthereof. Preferably, the solvent is a mixture consisting of dimethylformamide and water and comprises 10-50 vol %, preferably 30-50 vol %,more preferably 40-50 vol % of water, based on a total volume of thesolvent. A volume of the solvent may be in a range of 1-20 ml,preferably 1-10 ml, more preferably 1-5 ml.

In a preferred embodiment, the arylboronic acid/ester comprises ahydroxy, amine, or a thiol substituent and may be further substitutedwith the aforementioned substituents (e.g. R₆). Preferably, thearylboronic acid/ester is preferably a para-substituted phenylboronicacid, most preferably 4-hydroxy phenylboronic acid. An amount of theprecursor halogen substituted phenyl bisoxazoline ligand may be in arange of 0.1-10 mmol, preferably 0.1-3 mmol, more preferably 0.1-1 mmol.An amount of the palladium(II) salt or Pd⁺² source may be in a range of1-20 mol %, preferably 1-10 mol %, more preferably 4-6 mol %, based onthe number of moles of the precursor halogen substituted phenylbisoxazoline ligand. An amount of the base, preferably potassiumcarbonate may be in a range of 1-10 molar equivalents, more preferably1-5 molar equivalents, more preferably 1-3 molar equivalents of theamount of the precursor halogen substituted phenyl bisoxazoline ligand.An amount of the arylboronic acid/ester may be in a range of 1-10 molarequivalents, more preferably 1-2 molar equivalents, more preferably1-1.5 molar equivalents of the amount of the precursor halogensubstituted phenyl bisoxazoline ligand. The ligand may be isolated andpurified by methods known to those skilled in the art, such asfiltration through a celite containing cartridge, aqueous work-up,extraction with organic solvents, distillation, crystallization, columnchromatography, and high pressure liquid chromatography (HPLC) on normalphase or reversed phase. The yield of the functionalized diphenylbisoxazoline ligand is at least 50%, preferably at least 75%, morepreferably at least 80%.

In another step, the functionalized diphenyl bisoxazoline ligand reactswith a second base in the presence of the solid support to form thesolid-supported catalyst ligand. In a preferred embodiment, thefunctionalized diphenyl bisoxazoline ligand is a compound of formula(VII)

or a salt, solvate, tautomer or stereoisomer thereof wherein R₁, R₂, R₃and R₄ are independently —H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, or an optionally substituted aryl,each R₅ and R₆ is independently —H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, or an optionally substituted aryl, nis 1 with the proviso that X is O or S or n is 2 with the proviso that Xis N, preferably R₁ is —CH₃, R₂ is —CH₃, R₃ is —H, R₄ is —H, R₅ is —H,R₆ is —H, n is 1, and X is O and the functionalized diphenylbisoxazoline ligand of formula (VII) is

3,4′-Bis(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl)biphenyl-4-ol or thefunctionalized diphenyl bis(oxazoline) precursor ligand (BOX-2).

A second base, preferably a an alkali hydride, preferably sodium hydridemay be added to a solution of the functionalized diphenyl bisoxazolineligand in a dry organic solvent to form a mixture which is stirred for1-10 hours, preferably 1-5 hours, more preferably 1-3 hours at atemperature in a range of 15-50° C., preferably 20-40° C., morepreferably 20-30° C. under an inert atmosphere provided by nitrogen gas,helium gas, argon gas, or mixtures thereof. An amount of thefunctionalized diphenyl bisoxazoline ligand may range from 0.1-5 mmol,preferably 0.1-1 mmol, more preferably 0.1-0.5 mmol. An amount of thesecond base, preferably an alkali hydride, may be in a range of 1-10molar equivalents, more preferably 1-5 molar equivalents, morepreferably 1-2 molar equivalents of the amount of the functionalizeddiphenyl bisoxazoline ligand. Preferably, the second base is sodiumhydride. The solid support particle is then added to the mixture andthen stirred at a temperature in a range of 40-150° C., preferably40-100° C., more preferably 80-100° C. for 1-96 hours, preferably 1-48hours, more preferably 10-20 hours. The solid-supported catalyst ligandof formula (I) may be isolated and purified by methods known to thoseskilled in the art, such as filtration through a celite containingcartridge. The solid-supported catalyst ligand may also be washed withsolvents, such as methanol, water, acetone, and dichloromethane, anddried under reduced pressure (e.g. 0.1-50 mbar, preferably 0.1-10 mbar,more preferably 0.1-1 mbar). The yield of the solid-supported catalystligand is at least 70%, preferably at least 80%, more preferably atleast 90%.

In a preferred embodiment, the method may further comprise stirring thesolid-supported catalyst ligand of formula (I) in the presence of apalladium (II) salt to form the catalyst composition, solid-supportedpalladium (11) complex, or solid supported catalyst of formula (II). Thesolid-supported catalyst ligand of formula (I) may be suspended andstirred in a dry organic solvent (e.g. toluene, benzene, dimethylsulfoxide, tetrahydrofuran, or mixtures thereof) for 5-120 minutes,preferably 5-90 minutes, more preferably 10-60 minutes. An amount of thesolid-supported catalyst ligand is in a range of 0.1-5 mmol, preferably0.1-3 mmol, more preferably 0.1-1 mmol. A solution of a palladium (II)salt, as described herein and previously described, preferablybis(benzonitrile) palladium (II) chloride, in the same solvent is addedto the solid-supported catalyst ligand and the resulting mixture may bestirred at a temperature in a range of 40-150° C., preferably 40-100°C., more preferably 80-100° C. for 1-96 hours, preferably 1-48 hours,more preferably 10-20 hours. A molar ratio of the solid-supportedcatalyst ligand to the palladium (II) salt is in a range of 1:1 to 1:2,preferably 1:1 to 2:3, more preferably 1:1 to 1:1.2. The solid-supportedcatalyst or catalyst composition may also be washed with solvents, suchas ethanol, methanol, water, acetone, and dichloromethane, and driedunder reduced pressure (e.g. 0.1-50 mbar, preferably 0.1-10 mbar, morepreferably 0.1-1 mbar). The yield of the solid-supported catalyst orcatalyst composition is at least 70%, preferably at least 80%, morepreferably at least 90%, most preferably at least 95%.

According to a fourth aspect, the present disclosure relates to a methodfor a palladium cross-coupling reaction comprising reacting an arylhalide with a compound comprising a boronic acid, a terminal alkyne, oran alkene or derivatives thereof in the presence of a solvent, a base,and the catalyst composition to form a palladium cross-coupling productor derivatives thereof.

As used herein, a palladium cross-coupling reaction orpalladium-catalyzed coupling reactions comprises a family ofcross-coupling reactions that employ palladium complexes as catalysts.The reactions generally obey the stoichiometry of formula (VIII)

X—R+M-R″→MX+R-R″  (VIII)

Exemplary palladium cross-coupling reactions include, but are notlimited to, a Neigishi coupling between an organohalide and anorganozinc compound, a Heck reaction between alkenes and aryl halides, aSuzuki reaction between aryl halides and boronic acids, a Stillereaction between organohalides and organotin compounds, a Hiyamacoupling between organohalides and organosilicon compounds, aSonogashira coupling between aryl halides and alkynes, optionally withcopper(I) iodide as a co-catalyst, a Ruchwald-Hartwig amination of anaryl halide with an amine, optionally extended to aryl halide withphenol and thiol, a Kumada coupling of grignards and aryl or vinylhalides, a Heck-Matsuda reaction of an arenediazonium salt with analkene, and the like.

In a preferred embodiment, the palladium cross-coupling reaction is atleast one selected from the group consisting of a Suzuki-Miyaurareaction, a Mizoroki-Heck reaction, and a Sonagashira reaction. As usedherein, the Suzuki-Miyaura, or the Suzuki reaction is an organicreaction classified as a coupling reaction between a boronic acid and anorganohalide catalyzed by a palladium complex. It is widely used tosynthesize palladium cross-coupling products including, but not limitedto poly-olefins, styrene, and substituted biphenyls. Generally, acarbon-carbon single bond is formed by coupling an organoboron specieswith a halide using a palladium catalyst and a base. As used herein, theMizoroki-Heck, or Heck reaction is the chemical reaction of anunsaturated halide, or triflate, with an alkene in the presence of abase and a palladium catalyst to form a substituted alkene. As usedherein, the Sonagashira reaction is a cross-coupling reaction employinga palladium catalyst to form a carbon-carbon bond between a terminalalkyne and aryl or vinyl halide.

As used herein, the aryl halide comprises an optionally substituted arylgroup which may comprise the aforementioned substituents. Preferably,the aryl group is phenyl. In a preferred embodiment, the substituentsare electron-donating groups such as amino, alkoxyl, and alkyl. Inanother preferred embodiment, the substituents are electron-withdrawinggroups such as nitro, cyano, and acetyl. The aryl group may comprise upto 5 substituents. Preferably, there is one substituent. The substituentmay be located ortho, meta, or para to the halogen atom. Preferably, thesubstituent is located para to the halogen atom. The aryl halide may bean aryl monohalide such as aryl chloride, aryl bromide, and aryl iodide.Preferably, the aryl monohalide is an aryl iodide such as iodobenzene.Exemplary aryl monohalide includes, without limitation, iodobenzene,4-iodoaniline, 4-iodoacetophenone, 4-iodobenzonitrile, 4-iodoanisole,bromobenzene, 4-bromoacetophenone, and 1-iodo-4-nitrobenzene. In anotherembodiment, the aryl halide is an aryl dihalide such as1,4-dichlorobenzene, 1,4-dibromobenzene, and 1,4-diiodobenzene.Preferably, the aryl halide is 1,4-diiodobenzenc. It is equallyenvisaged that other organohalides, vinyl halides, triflates (e.g. aryltriflate, benzyl triflate, or vinyl triflate), or tosylates (aryltosylate, benzyl tosylate, or vinyl tosylate) may be employed.

In a preferred embodiment, the aryl halide is at least one selected fromthe group consisting of iodobenzene, bromobenzene, chlorobenzene,1-iodo-4-nitrobenzene, 1-bromo-4-nitrobenzene, 1-chloro-4-nitrobenzene,1-iodo-4-methoxybenzene, 1-bromo-4-methoxybenzene,1-chloro-4-methoxybenzene, 1-iodo-4-methylbenzene,1-bromo-4-methylbenzene, 1-chloro-4-methylbenzene, 4-iodobenzoic acid,4-bromobenzoic acid, 4-chlorobenzoic acid, 4-iodoacetophenone,4-bromoacetophenone, 4-chloroacetophenone, 4-iodoaniline,4-bromoaniline, and 4-chloroaniline.

As used herein, a boronic acid is an alkyl or aryl substituted boricacid containing a carbon-boron bond belonging to the larger class ororganoboranes. Exemplary boronic acids include, but are not limited to,phenylboronic acid, 2-thienylboronic acid, methyl boronic acid,cis-propenylboronic acid, trans-propenyl boronic acid and the like. Itis equally envisaged that boronic esters and other organoborane speciesmay be employed. As used herein, terminal alkynes have the formula RC₂Hand examples include methylacetylene and acetylene. As used herein, analkene is an unsaturated hydrocarbon that contains at least onecarbon-carbon double bond. The boronic acid, the terminal alkyne, andthe alkene may be optionally substituted which may comprise theaforementioned substituents.

Preferably, the solid-supported catalyst system tolerates a variety offunctional groups on the halide and/or the boronic acid/terminalalkyne/alkene and derivatives thereof. That is, the solid-supportedcatalyst retains the aforementioned turnover number and turnoverfrequency regardless of the functional groups on the halides and/or theboronic acid/terminal alkyne/alkene

In certain embodiments, prior to the reacting, the method furthercomprises an adding step wherein the solid-supported catalyst orcatalyst composition is added to the organic solvent, followed by thereactants, the base, and water to form a reaction mixture. In anotherembodiment, the base is first dissolved in water to form a basicsolution, which is then added to the other compounds in the organicsolvent. In one embodiment, the solid-supported catalyst is notpreformed but is formed in situ in a reaction flask (i.e. at least oneof the aforementioned palladium (II) salts and the solid-supportedcatalyst ligand of formula (I) are added to the reaction flaskseparately). Preferably, the adding step is performed in air. In anotherembodiment, the adding step is performed in an inert atmosphere providedby an inert gas such as argon, nitrogen, helium, or mixtures thereof.

In a preferred embodiment, the solvent may comprise 5-95% by volume ofwater and 5-95% by volume of an organic solvent, based on a total volumeof the solvent. Preferably, the solvent comprises 30-70% by volume ofwater and 30-70% by volume of an organic solvent, based on the totalvolume of the solvent. Most preferably, the solvent consists of 50% byvolume of water and 50% by volume of the organic solvent, based on thetotal volume of the solvent. Preferably, deionized distilled water isused. Preferably, the organic solvent is a polar aprotic solvent, morepreferably dimethylformamide or acetonitrile.

In a preferred embodiment, the aryl halide or vinyl halide is thelimiting reagent in the palladium cross-coupling reaction. An amount ofthe aryl halide may be in a range of 0.5-20 mmol, preferably 0.5-10mmol, more preferably 0.5-5 mmol. An amount of the boronic acid,terminal alkyne or alkene or derivatives thereof may be in a range of0.5-100 mmol, preferably 0.5-50 mmol, more preferably 0.5-25 mmol, or1-5 molar equivalents, preferably 1-3 molar equivalents, more preferably1-2 molar equivalents of the amount of aryl halide or vinyl halide. Anamount of the base may be in a range of 0.5-100 mmol, preferably 0.5-50mmol, more preferably 1-25 mmol, or 1-5 molar equivalents, preferably1-3 molar equivalents, more preferably 2-3 molar equivalents of theamount of aryl halide or vinyl halide.

In a preferred embodiment, an amount of the solid-supported catalyst mayrange from 0.001-10 mol % of a number of moles of the aryl halide orvinyl halide, more preferably 0.005-5 mol %, more preferably 0.01-2 mol%, more preferably 0.1-1.0 mol %, although higher catalyst loadings(e.g. up to 20 mol %, 30 mol %, 40 mol %, 80 mol %) may be used and themethod will still proceed as intended. In a preferred embodiment, themolar ratio of the aryl halide or vinyl halide to the catalystcomposition or solid-supported catalyst is greater than 100, preferablygreater than 200, preferably greater than 400, preferably greater than500.

In a preferred embodiment, the reacting may be performed at atemperature in a range of 35-110° C., preferably 50-110° C., morepreferably 70-100° C. An external heat source, such as a water bath oran oil bath, an oven, microwave, or a heating mantle, may be employed toheat the reaction mixture. In a preferred embodiment, the external heatsource is a thermostatted thermocirculator. In one embodiment, theaqueous solution is not heated with microwave irradiation. Preferably,the reacting is performed in air. In another embodiment, the reacting isperformed in an inert atmosphere provided by the aforementioned inertgases.

In a preferred embodiment, the reacting is performed for a time periodin the range from 0.5-24 hours, preferably 1-12 hours, more preferably2-8 hours, more preferably 4-6 hours. The reaction may be shaken/stirredthroughout the duration of the reaction by employing a rotary shaker, amagnetic stirrer, or an overhead stirrer. In another embodiment, thereaction mixture is left to stand (i.e. not stirred). In one embodiment,the reaction mixture is preferably mixed in a centrifugal mixer with arotational speed of at least 500 rpm, preferably at least 800 rpm, morepreferably at least 1,000 rpm, even though it can also be mixed with aspatula. In one embodiment, the reaction mixture is sonicated during themixing.

The reaction mixture is preferably heterogeneous and comprises suspendedsolid-supported catalyst particles in the liquid reaction mixture. Inone embodiment, the solid-supported catalyst particles may be dispersedwithin the reaction mixture, and may further be filtered and recycled atthe end of the reaction. In one embodiment, the solid-supported catalystis placed in a bag or semi-permeable membrane and the bag is immersed inthe reaction mixture. Accordingly, the solid-supported catalyst remainsin the bag or semi-permeable membrane until the coupling reaction iscompleted. The membrane that is required for this technique shall alloweasy transportation of both reactants and products yet have a pore sizethat ensures retention of the catalyst.

In certain embodiments, the progress of each reaction may be monitoredby methods known to those skilled in the art, such as thin layerchromatography, gas chromatography, nuclear magnetic resonance, infraredspectroscopy, and high pressure liquid chromatography combined withultraviolet detection or mass spectroscopy. Preferably, thin layerchromatography and gas chromatography combined with mass spectroscopyare used.

The palladium cross-coupling products and compounds obtained by themethod of the present disclosure are isolated and purified by employingthe aforementioned methods which are well-known to those skilled in theart. The isolated yield of the palladium cross-coupling product orderivatives thereof is at least 75%, preferably at least 80%, preferablyat least 90%, more preferably at least 92%, based on the initial molaramount of the aryl halide. The palladium cross-coupling product orderivatives thereof, resulting either from a single run or a combinationof runs, comprises less than 10 ppb palladium (measured by ICP-MS),preferably less than 5 ppb, more preferably less than 1 ppb, based on atotal weight of the palladium cross-coupling product or derivativesthereof. In a preferred embodiment, less than less than 0.5% of thetotal palladium by weight on the solid-supported catalyst was leachedinto the products, preferably less than 0.25%, preferably less than0.10%, preferably less than 0.05%, preferably less than 0.01%.

In a preferred embodiment, the method further comprises i) separatingthe catalyst composition from the palladium cross-coupling product orderivatives thereof to recover the catalyst composition, and ii) reusingthe catalyst composition in at least 2 reaction cycles with a less than5% decrease in at least one selected from the group consisting ofcatalytic activity, a molar yield of the palladium cross-couplingproduct, or a weight percentage of Pd metal relative to the total weightof the catalyst composition.

In certain embodiments, the solid-supported catalyst may be separated byremoving the bag of solid-supported catalyst, dialysis in a solvent, orusing a micro-filter or a paper filter. The phrase “recycling thesolid-supported catalyst” refers to a process whereby thesolid-supported catalyst or catalyst composition is first washed by anorganic solvent, dried, and then added to a new batch of reactants(either for the same or a different type of coupling reaction).Preferred organic solvents for washing the solid-supported catalystand/or dialysis may include, without limitation, methanol, acetone,ethanol, tetrahydrofuran, acetonitrile, dichloromethane, ether, glycolether, acetamide, dimethyl acetamide, dimethyl sulfoxide, orcombinations thereof. The solid-supported catalyst or catalystcomposition may be dried in vacuum, and/or with heating, for example,the catalyst may be dried in a vacuum oven. Dried solid-supportedcatalyst or catalyst composition may be stored in a desiccator until thenext run.

In a preferred embodiment, a turnover number of the catalyst compositionafter at least 8 reaction cycles, preferably at least 10 cycles,preferably at least 12 cycles, preferably at least 15 cycles morepreferably at least 20 cycles, even more preferably at least 30 cyclesis in the range of 1500-2500, preferably 1500-2000, preferably 1700-2000and a turnover frequency of the catalyst composition after at least 8reaction cycles, preferably at least 10 cycles, preferably at least 12cycles, preferably at least 15 cycles more preferably at least 20cycles, even more preferably at least 30 cycles in the range of 200-1500cycles per hour, preferably 200-1000 cycles per hour, more preferably200-500 cycles per hour

In one embodiment, the solid-supported catalyst or catalyst compositionis recycled for at least 2 reaction cycles, preferably at least 5cycles, preferably at least 8 cycles, preferably at least 10 cycles,preferably at least 12 cycles, preferably at least 15 cycles morepreferably at least 20 cycles, even more preferably at least 30 cycles.The catalyst composition may lose less than 5 wt %, preferably less than2 wt %, more preferably less than 0.1 wt % of palladium (based on aninitial amount of palladium present in the solid-supported catalyst andthe total weight of the catalyst composition) after the solid-supportedcatalyst is used for at least 2 reaction cycles, preferably at least 10cycles, more preferably at least 20 cycles, even more preferably atleast 30 cycles. The yield of the palladium cross-coupling product fromthe coupling reaction may decrease less than 20 percentage points,preferably less than 10 percentage points, more preferably less than 5percentage points, preferably less than 2 percentage points after thesolid-supported catalyst is used for at least 2 reaction cycles,preferably at least 10 cycles, more preferably at least 20 cycles, evenmore preferably at least 30 cycles. The turnover number and the turnoverfrequency of the solid-supported catalyst or catalyst composition maydecrease by less than 10%, preferably less than 5%, more preferably lessthan 2% after the solid-supported catalyst is used for at least 2reaction cycles, preferably at least 10 cycles, more preferably at least20 cycles, even more preferably at least 30 cycles.

In one embodiment, the catalytic composition or solid-supported catalystmay comprise the solid-supported catalyst ligand chelating rhodium andbe employed in a chemical transformation such as a hydrogenation orhydroformylation. In one embodiment, the hydrogenation may be anasymmetric hydrogentation. Exemplary rhodium catalyzed hydrogenationsinclude, but are not limited to, the hydrogenation of alkenes, thehydrogenation of alkynes, the hydrogenation of aromatic cyclic arenes,the hydrogenation of nitriles, and the hydrogenation of pyridines andN-heterocycles.

In one embodiment, the catalytic composition or solid-supported catalystmay comprise the solid-supported catalyst ligand chelating palladiumand/or platinum and be employed in a chemical transformation such as theselective oxidation of alcohols and aldehydes or allylic alkylations. Inone embodiment, the catalytic composition or solid-supported catalystmay comprise the solid-supported catalyst ligand chelating palladium orruthenium and be employed in a chemical transformation such as Heckarylations and vinylations, Tsuji-Trost reactions (additions toπ-allyls), olefin metathesis and/or aromatic carbon-heteroatom bondforming reactions.

The examples below are intended to further illustrate protocols forpreparing and characterizing the solid-supported catalyst ligands andcatalyst compositions of the present disclosure. Further, they areintended to illustrate assessing the properties of these materials andassessing their performance in palladium cross-coupling reactions. Theyare not intended to limit the scope of the claims.

Example 1 Synthesis of bis(oxazoline) ligand2,2′-(4-Iodobenzene-1,2-diyl)bis(4,4-dimethyl-4,5-dihydro-1,3-oxazole)(BOX-1)

The iodo functionalized ligand (BOX-1) was prepared. FIG. 1 shows thescheme for this preparation starting from the reaction of4-iodophthalonitrile with 2 mol equivalents of2-amino-2-methyl-1-propanol. The BOX ligand was prepared in accordancewith an earlier published procedure by the inventors for similarhomogeneous catalysts [M. B. Ibrahim, B. El Ali, M. Fettouhi, L. Ouahab,Appl. Organometal. Chem, 2015, 29, 400; and M. B. Ibrahim, S. M. ShakilHussain, A. Fazal, M. Fettouhi, B. El Ali, J. Coord. Chem. 2015, 68:3,432; and S. M. Shakil-Hussein, M. B. Ibrahim, A. Fazal, R. Suleiman, M.Fettouhi and B. El Ali, Polyhedron, 2014, 70, 39.—each incorporatedherein by reference in its entirety]. A solution of 4-iodophthalonitrile(4.0 mmol) and zinc triflate (5.0 mol %, 0.2 mmol) in driedchlorobenzene (30 mL) was stirred at room temperature for 15 minutes. Asolution of 2-amino-2-methyl-1-propanol (8.0 mmol) in dry chlorobenzene(5 mL) was slowly added. The temperature was raised to 135° C. and thereaction mixture was refluxed for 24 hours. The solvent was removedusing a rotary evaporator. The crude product was dissolved in 30 mL ofdichloromethane and extracted twice with distilled water (2×20.0 mL).The aqueous layer was then separated and the combined organic layerswere dried with anhydrous sodium sulfate. The dichloromethane wasremoved was removed using a rotary evaporator to obtain the impureproduct, which was then purified using silica gel column chromatographywith dichloromethane-ether (4:1) as eluent.

Yield 94%; waxy solid; ¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.01 (s, 1H, C-3aromatic), 7.73 (d, J=10 Hz, 1H, C-5 aromatic), 7.38 (d, J=10 Hz, 1H,C-6 aromatic), 3.99 (s, 2H, OCH₂), 3.98 (s, 2H, OCH₂), 1.30 (s, 6H,CH₃×2); 1.29 (s, 6H, CH₃×2); ¹³C NMR (125 MHz, CDCl₃) δ (ppm); 27.95(CH₃×4), 67.92 (NCH×2), 79.40 (OCH₂×2), 96.12 (C-4 aromatic), 127.89(C-1 aromatic), 130.11 (C-2 aromatic), 130.97 (C-6 aromatic), 138.26(C-5 aromatic), 139.07 (C-3 aromatic), 160.82 (C-4′), 161.47 (C-1′); IR(KBr) ν (cm⁻¹) 2963, 2884, 1642, 1458, 1398, 1352, 1303, 1194, 1089,1039, 964, 824, 723; GC-MS m/z 398 (M+); Anal. Calc. for C₆H₁₉IN₂O₂(398.24): C, 48.26; H, 4.81; N, 7.03. Found: C, 48.44; H, 4.88; N, 7.22.

Example 2 Synthesis of hydroxyl functionalized bis(oxazoline) ligand3,4′-Bis(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl)biphenyl-4-ol (BOX-2)

The hydroxyl functionalized ligand (BOX-2) was prepared from theSuzuki-Miyaura cross coupling reaction of BOX-1 with 4-hydroxyphenylboronic acid (FIG. 1).2,2′-(4-Iodobenzene-1,2-diyl)bis(4,4-dimethyl-4,5-dihydro-1,3-oxazole)(BOX-1) (0.50 mmol), PdCl₂ (0.025 mmol, 5.0 mol %), K₂CO₃ (1.0 mmol, 2.0mol equivalent), DMF (2 mL), distilled water (2 mL) and 4-hydroxyphenylboronic acid (0.6 mmol), were added together in a 10 mL roundbottom flask. The mixture was stirred at 70° C. for 6 hours. Aftercompletion of the reaction, the mixture was cooled down and acidifiedwith IM HCl. The acidified solution was extracted 3 times with Et-OAcand the combined Et-OAc extracts were dried using anhydrous MgSO4. Thesolvent was removed under reduced pressure and the product was purifiedby silica gel column chromatography using hexane-EtOAc (1:9) as aneluent.

Yield 94%; Light brown oil; ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.81 (s,1H), 7.79 (d, J=10 Hz, 1H), 7.57 (d, J=10 Hz, 1H), 7.25 (s, 2H), 6.82(d, J=10 Hz, 2H), 4.18 (s, 2H, OCH₂), 4.14 (s, 2H, OCH₂), 1.51 (s, 6H,NC(CH₃)₂), 1.44 (s, 6H, NC(CH₃)₂); ¹³C NMR (125 MHz, CDCl₃) δ (ppm);28.0 (NC(CH₃)₂), 28.1 (NC(CH₃)₂), 67.7 (NC(CH₃)₂), 67.9 (NC(CH₃)₂), 79.6(OCH₂), 79.9 (OCH₂), 116.1, 116.2, 125.7, 127.9, 128.2, 130.3, 130.4,143.4, 157.3, 162.5, 164.1; IR (CH₂Cl₂) ν (cm⁻¹) 3189, 2968, 2929, 2893,1650, 1605, 1522, 1460, 1358, 1276, 1177, 1098, 964, 829. GC-MS m/z 364(M⁺); Anal. Calc. for C₂₂H₂₄N₂O₃ (364.44): C, 72.51; H, 6.64; N, 7.69.Found: C, 72.25; H, 6.38; 1; N, 7.52.

Example 3 Synthesis of Supported Bis(Oxazoline) Ligand on MerrifieldResin (BOX-3) and Palladium (II) Bis(Oxazoline) Supported on MerrifieldResin (Pd-BOX)

The functionalization of Merrifield resin with the bis(oxazoline) ligand(BOX-2) to form Merrifield resin supported BOX ligand (BOX-3) (FIG. 1)followed by subsequent complexation with palladium chloride to form thepolymer supported palladium bis(oxazoline) catalyst (Pd-BOX). FIG. 2shows the shows the scheme for this preparation. NaH (0.5 mmol) wasadded in one portion to a stirred solution of3,4′-Bis(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl)biphenyl-4-ol (BOX-2)(0.30 mmol) in dry DMF in a dry flask. The mixture was stirred for 2hours at room temperature and under an argon atmosphere. Merrifieldresin (0.30 mmol) was added and the mixture was stirred at 90° C. for 12hours. The solid product was filtered and washed successively withmethanol, water, acetone, and dichloromethane. The product was dried atroom temperature under vacuum. Yellow solid; 91% yield; ¹³C NMR: δ 28.2,41.7, 67.9, 80.3, 91.4, 120-140 (several signals), 168.8; IR: ν_(max)(cm⁻¹) 3081, 3024, 2965, 2923, 1652, 1604, 1517, 1491, 1452, 1351, 1311,1244, 1086, 1036, 825, 759, 699, Anal. C, 80.68; H, 6.36; N, 3.80.

The Merrifield resin supported bis(oxazoline) ligand (BOX-3) (0.3 mmol)was stirred in anhydrous ethanol for 30 minutes. An ethanolic solutionof bis(benzonitrile) palladium (II) chloride (0.3 mmol) was added andthe resulting mixture was stirred at 50° C. for 12 hours. The solidproduct was filtered, washed thoroughly with ethanol and dried in vacuum[M. Bakherad, B. Bahramian, H. Nasr-Isfahani, A. Kievanloo, G. Sang,Chin. J. Chem. 2009, 27, 353.—incorporated herein by reference in itsentirety]. Dark brown solid, 95% yield; ¹³C NMR: δ 27.5, 41.4, 70.5,81.7, 96.1, 120-140 (several signals), 182.3; IR: ν_(max) (cm⁻¹) 3056,3021, 2919, 2844, 1634, 1599, 1494, 1452, 1371, 1327, 1221, 1178, 1068,1011, 950, 824, 757, 699; Anal. C, 62.84; H, 4.83; N, 2.99. Metalloading from ICP-MS: 6.7% corresponding to 0.6 mmol/g.

Example 4 Characterization and Analysis of Prepared SupportedBis(Oxazoline) Ligands, Intermediates and Supported PalladiumBis(Oxazoline) Catalysts

The BOX ligands (BOX-1 and BOX-2) were characterized using analyticaland spectroscopic techniques. The molecular weight of BOX-1 and BOX-2were established using gas chromatography mass spectrometry (GC-MS). The¹H and ¹³C nuclear magnetic resonance (NMR) chemical shifts for the BOXligands were consistent with their proposed structures and were inentire agreement with the characterization data of other knownbis(oxazoline) ligands. The Fourier transform infrared (FT-IR) spectraldata for both BOX-1 and BOX-2 ligands further confirmed their proposedstructures. The formation of the expected supported bis(oxazoline)ligand on Merrifield resin (BOX-3) and palladium (II) bis(oxazoline)supported on Merrifield resin (Pd-BOX) products were confirmed by FT-IR,cross-polarization magic angle spinning nuclear magnetic resonance(CP-MAS NMR), elemental analysis and inductively coupled plasma massspectrometry (ICP-MS).

The sharp C—Cl peak at 1264 cm⁻¹ which was observed in the FT-IRspectrum of the unmodified Merrifield resin is no longer present afterthe introduction of the bis(oxazoline) ligand and the complexation withpalladium chloride. This is consistent with the fact that substantiallyall of the chloro groups attached to the resin were successfullyreplaced with the BOX ligand. The formation of the resin supportedbis(oxazoline) ligand was further confirmed by the appearance of astrong band at 1652 cm⁻¹ without palladium and at 1634 cm⁻¹ due to thecomplexation with palladium. This peak was initially absent in thespectrum of the unmodified Merrifield resin. This band is attributed tothe stretching of the imino (—C═N—) bond of the oxazoline ring. Theshift in the position of the imino band (Δv=18 cm−1) confirms thecoordination of palladium with the supported ligand. The position of theimino band in the supported ligand and the observed shift aftercoordination with palladium, entirely agrees with the previouslyreported literature [R. Antony, G. L. Tembe, M. Ravindranathan, R. N.Ram, J. Appl. Polym. Sci., 2003, 90, 370.—incorporated herein byreference in its entirety].

Solid state NMR data of the polymer bound to the ligand and itspalladium catalyst were in entire agreement with the data reported forother homogenous and supported bis(oxazoline) ligands and catalysts [M.S. Sarkar, M. L. Rahman, M. M. Yusoff, RSC Adv. 2015, 5,1295.—incorporated herein by reference in its entirety]. The palladiumloading on the polymer supported palladium catalyst which was analyzedusing ICP-MS, was estimate as 6.7% (0.6 mmol/g). The thermal stabilityof both the resin supported ligand and its palladium catalyst wasestablished from thermogravimetric analysis (TGA). The Merrifield resinsupported bis(oxazoline) ligand and its palladium catalyst form werefound to possess high thermal stability with a decomposition temperaturegreater than 350° C. In the X-ray photoelectron spectroscopy (XPS)spectrum of the supported catalyst, palladium peaks were observed in therange of 335 to 341 eV. Two distinctive 3d peaks were identified, thefirst peak with binding energy of 334.98 eV (Pd3d_(5/2)) and the secondpeak with binding energy of 340.28 (Pd3d_(3/2)). These peaks correspondto palladium (II) forms, and this confirms that palladium (II) is themain form of palladium in the supported catalyst.

In order to assess the morphology of the Merrifield resin, Merrifieldresin supported bis(oxazoline) ligand (BOX-3) and the Merrifield resinsupported dichloridopalladium (II) bis(oxzaoline) complex (Pd-BOX),scanning electron microscopy (SEM) micrographs were recorded for asingle bead of pure Merrifield resin (FIG. 3), the supportedbis(oxazoline) ligand (FIG. 4), and the supported dichloridopalladium(II) catalyst (FIG. 5). Expectedly, the smooth and flat microspheresurfaces of the Merrifield resin have been broken into a rough andirregular surface after incorporation of the bis(oxazoline) ligand andthen the palladium bis(oxazoline) catalyst. The morphological changesobserved were similar to what has been previously reported in theliterature for other polystyrene supported ligands and their palladiumcatalyst [M. Bakherad, A. Keivanloo, B. Bahramian, S. Jajarmi, Appl.Catal. A: General 2010, 390, 135.—incorporated herein by reference inits entirety].

Example 5 Catalytic Activity of Palladium Bis(Oxazoline) Supported onMerrifield Resin (Pd-BOX) in Suzuki-Miyaura Cross Coupling Reactions

The activity of the prepared supported catalyst in the Suzuki-Miyauracross coupling reaction of arylbornoic acids and aryl halides wascarefully examined. In general, the Suzuki-Miyaura coupling reaction,which is catalyzed by supported palladium catalysts, follows a similarmechanism to that of the homogeneous catalyst [M. S. Sarkar, M. L.Rahman, M. M. Yusoff, RSC Adv. 2015, 5, 1295.—incorporated herein byreference in its entirety]. For this reason, previously optimizedreaction conditions were adopted based on homogeneous palladiumbis(oxazoline) catalysts ([Pd]/K₂CO₃/DMF-H₂O). Several arylboronic acidswith aryl iodides, aryl bromides, and aryl chlorides were considered inthis reaction.

In a general procedure for Suzuki-Miyaura cross coupling reaction arylhalide (1.0 mmol), aryl boronic acid (1.2 mmol), potassium carbonate(2.0 mmol), DMF (3.0 mL) and distilled water (3.0 mL) were addedtogether in a 10 mL round bottom flask. Immobilized palladiumbis(oxazoline) catalyst contained in a dialysis bag (0.0050 mmol) wasintroduced. The mixture was stirred at 80° C. The progress of thereaction was monitored by gas chromatography. After completion of thereaction, the catalyst bag was removed and dialyzed in DMF to extractall the products. The combined solutions were extracted with ethylacetate. The combined ethyl acetate extracts were dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure usinga rotary evaporator. The crude product was purified by silica gel columnchromatography using hexane-EtOAc as eluent.

The recycling ability of the prepared supported palladium bis(oxazoline)catalyst in DMF-H₂O was investigated in the Suzuki-Miyaura crosscoupling reaction of iodobenzene with p-tolylboronic acid at 80° C. for2 hours (FIG. 6). The supported catalyst was packaged in a membrane tubefabricated from a commercially available dialysis bag. The membraneallows the migration of molecules with low molecular weight. This meansthat only the reactants and products can smoothly pass through it. Thetransport of both reactants and products into and out of the membrane isdriven by the concentration gradient and temperature of the reaction(80° C.) [M. Gaab, S. Bellemin-Laponnaz, L. H. Gade, Chem. Eur. J. 2009,15, 5450; and J. S. Willemsen, J. C. M. Van-Hest, F. P. J. T. Rutjes,Beilstein J. Org. Chem. 2013, 9, 960.—each incorporated herein byreference in its entirety]. FIG. 7 presents the results of the recyclingexperiments. Remarkably, the supported catalyst could be recycled up totwelve times without bearing any loss in its catalytic activity. Theturnover number was estimated for the 12 reaction cycles as 2242, whilethe turnover frequency was estimated as 1121/h. In order to confirm theefficiency of the supported catalyst, an experimental run was conductedwith a ratio of iodobenzene (12.0 mmol) to supported palladiumbis(oxazoline) catalyst (0.005 mmol) equal to 2400 for 2 hours. Acomplete conversion of iodobenzene and an excellent isolated yield (98%)of the coupling product was obtained. The turnover number of thesupported palladium-bis(oxazoline) catalyst in this experimental run wasestimated as 2353, while the turnover frequency was estimated as 1176/h.

Previous studies by the inventors have established that the homogeneousPd-BOX complexes exhibit high activities for the Suzuki-Miyaura couplingof diversely functionalized aryl halides including aryl iodide, arylbromides, and aryl chlorides with a wide array of arylboronic acids. Ithas been found that the homogeneous catalytic system is tolerant to awide variety of functional groups on both the aryl halides and thearylboronic acids. Previous studies related to the recycling ability ofsupported catalysts are restricted to the reaction of the samesubstrates throughout the catalytic cycles. In contrast, the presentdisclosure establishes a new method by recycling the used catalyst forall coupling reactions of different substrates. This means the samepalladium-BOX supported catalyst placed in a dialysis bag was used forall substrates indicated in the Table 1. Table 1 presents theSuzuki-Miyaura coupling reaction of various aryl halides with differentarylboronic acids using the prepared Pd-BOX supported catalyst. Therecycling ability of the prepared palladium supported catalyst wasapplied in the Suzuki-Miyaura cross coupling of a broad range ofsubstrates using DMF-H₂O (1:1) as a solvent system and K₂CO₃ as a base.Thus, different aryl halides including aryl iodides, aryl bromides andaryl chlorides were coupled successfully with various arylboronic acids(Table 1). At the end of each reaction, the catalyst contained in adialysis bag was removed from the reaction mixture, dialyzed in DMF toremove all the traces of reactants and products, and dried under openair conditions before being used in the next catalytic reaction with anew substrate.

TABLE 1 Results of Suzuki-Miyaura coupling reactions of various arylhalides with different arylboronic acids using the prepared Pd-BOXsupported catalyst

Entry Aryl Halide Aryl Boronic Acid Time (h) Yield (%)^(b) 1

2 96 2

2 94 3

2 95 4

4 92 5

3 94 6

5 90 7^(c)

12 95 8^(c)

12 92 ^(a)Reaction Conditions: [Pd] (0.005 mmol), aryl boronic acid (1.2mmol), aryl halide (1.0 mmol), K₂CO₃ (2.0 mmol), DMF (3.0 mL), H₂O (3.0mL), 80° C. ^(b)Isolated Yield. ^(c)110° C., using fresh catalyst.

Aryl iodides having either activating or deactivating groups reactedsmoothly, affording the cross coupling products in excellent isolatedyields (92-98%) (Table 1, entries 1-4). Various functional groups weretolerated with the prepared palladium supported catalysts. The couplingreactions were also successful with both activated and deactivated arylbromides leading to the corresponding biphenyl products in high isolatedyields (Table 1, entries 5-6). It is of note that all the reactions ofarylboronic acids with aryl iodides and aryl bromides were conductedwith the same recycled catalyst. Aryl chlorides were less reactive asanticipated and the reactions required a relatively higher temperature(110° C.). The coupling reactions of aryl chlorides were conducted usinga solid fresh catalyst and without dialysis bag. In addition, a longerreaction time (12 hours) was necessary to obtain high yields (Table 1,entries 7-8). The effect of varying the substituents on the arylboronicacids was also investigated. In contrast to aryl halides, the overallelectronic effect of the arylboronic acids with the supported palladiumbis(oxazoline) catalyzed Suzuki-Miyaura reaction was ratherinsignificant.

Example 6 Catalytic Activity of Palladium Bis(Oxazoline) Supported onMerrifield Resin (Pd-BOX) in Mizoroki-Heck Cross Coupling Reactions

The catalytic activities of the prepared supported palladiumbis(oxazoline) catalyst in Mizoroki-Heck coupling reactions of variousolefins and aryl halides was carefully examined. Previously optimizedreaction conditions were adopted based on homogeneous palladiumbis(oxazoline) catalysts ([Pd]/KOH/DMF-H₂O). In a general procedure forMizorok-Heck cross coupling reactions a mixture of aryl halide (1.0mmol), alkene (1.5 mmol), KOH (2.0 mmol), DMF (2.0 mL) and distilledwater (2.0 mL) was added together in a 10 mL round bottom flask.Immobilized palladium bix(oxazoline) catalyst contained in a dialysisbag (0.0050 mmol) was introduced. The mixture was stirred at 80° C. Theprogress of the reaction was monitored by gas chromatography. After thecompletion of the reaction, the catalyst bag was removed and dialyzed inDMF to extract all the products. The combined solutions were extractedwith ethyl acetate. The combined ethyl acetate extracts were dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure using a rotary evaporator. The crude product was purified bysilica gel column chromatography using hexane-EtOAc as an eluent.

The recycling ability of the prepared Merrifield resin supportedpalladium bis(oxazoline) catalyst in the Mizoroki-Heck coupling reactionof iodobenzene with styrene was examined (FIG. 8). Interestingly, thesupported catalyst could be recycled up to 10 times without significantloss in its catalytic activity. FIG. 9 presents the results of therecycling experiments. The turnover number of the Merrifield resinsupported palladium bis(oxazoline) catalyst was estimated for the 10reaction cycles as 1800, while the turnover frequency was found to be300/h. In order to confirm the efficiency of the Merrifield resinsupported palladium bis(oxazoline) catalyst, an experimental run wasconducted with a ratio of iodobenzene (10.0 mmol) to supported palladiumbis(oxazoline) catalyst (0.005 mmol) equal to 2000 for 6 hours. Asubstantially complete conversion of iodobenzene and excellent isolatedyield of product (93%) was observed. The turnover number of theMerrifield resin supported palladium bis(oxazoline) catalyst in thisexperimental run was estimated as 1860, while the turnover frequency wasfound as 310/h.

Previous studies by the inventors have reported that the homogeneouspalladium bis(oxazoline) catalysts exhibit high catalytic activity forthe Mizoroki-Heck coupling reaction of diversely functionalized aryliodides with a wide array of terminal alkenes. The homogeneous palladiumbis(oxazoline) catalyst previously reported, was capable of tolerating avariety of functional groups on both the aryl iodides and the alkenes.The high recycling ability realized with the prepared supported catalystin the Mizoroki-Heck cross coupling of iodobenzene with styreneencouraged an examination of the recycling ability of the supportedcatalysts in the Mizoroki-Heck coupling of a broad range of substratesusing DMF-H₂O (1:1) as a solvent system and KOH as a base. Thus, variousaryl halides including aryl iodides and aryl bromides were coupledsuccessfully with various styrene derivatives. Table 2 presents theMizoroki-Heck coupling reaction of various aryl halides with differentalkenes using the prepared Pd-BOX supported catalyst. At the end of eachreaction, the catalyst was removed from the reaction mixture anddialyzed in DMF to remove all traces of reactants and products beforebeing taken forward into a subsequent catalytic reaction run.

TABLE 2 Results of Mizorok-Heck coupling reactions of various arylhalides with different alkenes using the prepared Pd-BOX supportedcatalyst

Yield Entry Aryl Halide Alkene Coupling Product (%)^(b) 1

96 2

96 3

90 4

97 5

98 6^(c)

92 7^(c)

82 ^(a)Reaction Conditions: [Pd] (0.005 mmol), alkene (1.5 mmol), arylhalide (1.0 mmol), KOH (2.0 mmol), DMF (3.0 mL), H₂O (3.0 mL), 80° C., 6hours. ^(b)Isolated Yield. ^(c)reacted at 100° C.

Example 7 Catalytic Activity of Palladium Bis(Oxazoline) Supported onMerrifield Resin (Pd-BOX) in Sonogashira Cross Coupling Reactions

The catalytic activities of the prepared supported palladiumbis(oxazoline) catalysts in Sonogashira cross coupling reactions ofalkynes and aryl halides was investigated. Previously optimized reactionconditions were adopted based on the catalytic system of homogeneouspalladium bis(oxazoline) catalysts ([Pd]/KOH/CH₃CN—H₂O) [M. B. Ibrahim,B. El Ali, I. Malik, M. Fettouhi, Tetrahedron. Lett. 2015, 57,554.—incorporated herein by reference in its entirety]. The couplingreactions of various aryl iodides with aryl and alkyl alkynes wereconsidered in this reaction. In a general procedure for Sonogashiracross coupling reactions a mixture of aryl halide (1.0 mmol), alkyne(1.5 mmol), KOH (2.00 mmol), acetonitrile (2 mL) and distilled water (2mL) were added together to a flask. Immobilized palladium bis(oxazoline)catalyst contained in a dialysis bag (0.0050 mmol) was introduced. Themixture was stirred at 60° C. for the required time. After completion ofthe reaction, the catalyst bag was removed and dialyzed in acetonitrileto extract all the products. The combined solutions were extracted withethyl acetate. The combined ethyl acetate extracts were dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure in a rotary evaporator. The residue was purified using columnchromatography with hexane-EtOAc as eluent to afford the cross couplingproduct in an excellent yield.

The recycling ability of the prepared Merrifield resin supportedpalladium bis(oxazoline) catalyst in the Sonogashira cross couplingreaction of iodobenzene with phenylacetylene was examined (FIG. 10).Interestingly, the supported catalyst could be recycled up to ten timeswithout significant loss in its catalytic activity. FIG. 11 presents theresults of the recycling experiments. The turnover number of thesupported palladium bis(oxazoline) catalyst was estimated for the 10reaction cycles as 1802, while the turnover frequency was found to be300/h. In order to confirm the efficiency of the supported palladiumbis(oxazoline) catalyst, an experimental run was conducted with a ratioof iodobenzene (10.0 mmol) to supported palladium bis(oxazoline)catalyst (0.005 mmol) equal to 2000 for 6 hours. A substantiallycomplete conversion of iodobenzene and an excellent isolated yield ofproduct (96%) were observed. The turnover number of the supportedpalladium bis(oxazoline) catalyst in this experimental run was estimatedas 1920 while the turnover frequency was found to be 320/h.

The high recycling ability of the supported palladium bis(oxazoline)catalyst in the Sonogashira cross coupling reaction of iodobenzene withphenylacetylene suggested an extension of the scope of the couplingreaction to various electronically different aryl halides and alkynes.Table 3 presents the Sonogashira coupling reaction of various arylhalides with different alkynes using the prepared Pd-BOX supportedcatalyst. The Sonogashira coupling reaction of 4-iodoacetophenone withphenylacetylene was studied using the Merrifield resin supportedpalladium bis(oxazoline) catalyst. The corresponding internal acetylenewas obtained in almost quantitative yield (95%) (Table 3, entry 1). Thecatalyst was dialyzed in acetonitrile and the purified catalyst was usedagain for the coupling of iodobenzene with p-tolylacetylene.Interestingly, the reaction worked to give excellent yield (90%) of theexpected product (Table 3, entry 2). The same catalyst was then used inthe coupling of phenylacetylene with 4-iodoanisole and with4-iodoaniline (Table 3, entries 4 and 5). The corresponding internalacetylenes were also isolated in excellent yields (89% and 90%,respectively). The recycled catalyst was also evaluated in theSonogashira coupling reaction of iodobenzene with alkyl alkynes. Forexample, the coupling reaction of iodobenzene with 5-chloro-1-pentyneled to excellent yield (91%) of the coupling product (Table 3, entry 6).Similarly, 5-cyano-1-pentyne was successfully coupled with iodobenzene(93%) (Table 3, entry 7).

TABLE 3 Results of Sonogashira coupling reactions of various arylhalides with different alkynes using the prepared Pd-BOX supportedcatalyst

En- Time Yield try Aryl Halide Alkyne (h) (%)^(b) 1

2 95 2

4 90 3

4 94 4

5 89 5

5 90 6

12 91 7

12 93 ^(a)Reaction Conditions: [Pd] (0.005 mmol), alkyne (1.5 mmol),aryl halide (1.0 mmol), KOH (2.0 mmol), CH₃CN (2.0 mL), H₂O (2.0 mL),60° C. ^(b)Isolated Yield.

Example 8 General Procedure for and Characterization and Analysis of theRecycling of the Prepared Supported Palladium Bis(Oxazoline) CatalystsUsing a Dialysis Bag

The reusability of the supported palladium bis(oxazoline) catalyst wasstudied in a number of cross coupling reactions including theSuzuki-Miyaura, Mizoroki-Heck, and Sonogashira cross coupling reactions.In this procedure membrane piece was soaked in distilled water for 5minutes and squeezed open. The bag was tied from the bottom. Therequired quantity of the catalyst and a magnetic stir bar were placed inthe bag. The bag was then tied from the top. The catalyst bag was placedin a flask containing the appropriate reactants. The flask was mountedon a hot plate equipped with magnetic stirring. At the end of eachreaction cycle, the catalyst bag was removed from the reaction flask anddialyzed in the appropriate solvent to remove all traces of thereactants and product. The catalyst bag was then placed in another flaskcontaining fresh substrates for the subsequent run. The same cleaningprocedure was repeated after each cycle. After the sixth cycle, thecatalyst was removed from the dialysis bag, washed successively withwater, acetone, and methanol. The catalyst was dried in an oven at 100°C. and then place in a new dialysis bag and used in the subsequentcycles.

It was further necessary to characterize the recycled palladiumbis(oxazoline) supported catalysts. The ability to recycle theMerrifield resin supported palladium bis(oxazoline) catalyst for severalreaction cycles and in various cross coupling reactions withoutsignificant loss in its catalytic activity demonstrates its highstability and catalytic activity. The outstanding results obtained withthe supported catalysts suggested a further investigation in order toexamine and determine the change in the structure and composition of theused catalyst, if any, as compared with the fresh catalyst. Therecovered catalysts from the various cross coupling reactions werewashed successively with distilled water, acetone, and methanol. Thecatalysts were then dried in an oven at 100° C. prior to the analysis.The washed catalysts were analyzed using FT-IR and XPS and the amount ofpalladium loading was established using ICP-MS.

The FT-IR spectrum of the recovered Merrifield resin supported catalystwas found to be similar with the spectrum of the un-used catalyst. Thepercentage of palladium on the supported catalyst recovered from theSuzuki-Miyaura (6.0%) and the Mizorok-Heck (6.1%) cross couplingreaction was found to be almost similar to the amount of palladiumloading in the fresh catalyst (6.7%). These results further justify thehigh recycling ability observed with the new supported catalysts. TheXPS spectrum of the recovered catalyst shows that the oxidation state ofpalladium remains unchanged after the catalytic applications. Similar tothe un-used supported catalyst, the 3d spectrum, resolved in to 3d_(5/2)and 3d_(3/2) spin orbit pairs with binding energies of 334.58 eV and339.78 eV respectively [H. N. Yeap, W. Mian, H. Hong, L. L. C.Christina, Chem. Commun., 2009, 5530; and A. R. Hajipour, Z.Shirdashtzade, G. Azizi, J. Chem. Sci. 2014, 126, 1, 85.—eachincorporated herein by reference in its entirety].

In addition, leaching tests of the palladium bis(oxazoline) supportedcatalysts were performed. The main objective of supporting a homogeneouscatalyst is to enable its easy separation from the product and tominimize the level of contamination caused by leaching of the toxicmetal. The possibility of palladium leaching into the products wasanalyzed using ICP-MS. After recycling the catalyst, the solutions fromthe reaction were combined in various containers. The solution in eachcontainer was digested separately using concentrated nitric acid andwere analyzed using ICP-MS. The results from the ICP-MS analysisindicate that the concentration of palladium in the products was below10 ppb in each sample. These results indicate that less than 0.5% of thetotal palladium on the supported catalyst was leached into the products.This clearly indicates the high stability of the catalyst towards thecross coupling reactions under the current prescribed conditions.

A new palladium (II) bis(oxazoline) supported on Merrifield resin(Pd-BOX) as heterogeneous catalyst was synthesized and characterized.The new supported Pd-BOX catalyst showed excellent catalytic activity indifferent cross coupling reactions including Suzuki-Miyaura,Mizaroki-Heck, and Sonogashira reactions. The excellent catalyticactivity of the supported Pd-BOX catalyst was reflected by the highrecycling ability for more than 10 cycles without a significant loss inthe activity. Various biaryl, internal alkene and alkyne compounds havebeen synthesized in excellent isolated yields. The catalytic system cantolerate a wide range of substituents on the reactant aryl halides, arylboronic acids, styrene alkene derivatives and alkynes. Thecharacterization data of the used catalyst was found to be similar ifnot practically the same as that of the un-used catalyst, which reflectsthe high stability of the new heterogeneous palladium catalyst. Thesenew materials reported in this disclosure and prepared using the newpalladium catalyst system could be of high interest to most electronicdisplays, petrochemical and chemical feedstocks companies.

Thus, the foregoing discussion discloses and describes merely exemplaryembodiments of the present invention. As will be understood by thoseskilled in the art, the present invention may be embodied in otherspecific forms without departing from the spirit or essentialcharacteristics thereof. Accordingly, the disclosure of the presentinvention is intended to be illustrative, but not limiting of the scopeof the invention, as well as other claims. The disclosure, including anyreadily discernible variants of the teachings herein, defines, in part,the scope of the foregoing claim terminology such that no inventivesubject matter is dedicated to the public.

1-13. (canceled) 14: An aryl halide cross-coupling method, comprising:reacting the aryl halide with a compound comprising at least one of aboronic acid, a terminal alkyne, and an alkene in the presence of asolvent, a base, and a solid-supported catalyst to form a palladiumcross-coupling product, wherein the solid-supported catalyst, comprises:a catalytic metal in the form of a Pd⁺² species having the formula PdZ₂,wherein Z is selected from the group consisting of —Cl, —I, —Br, —OAcand —OTf, and a solid-supported ligand of formula (I)

wherein the nitrogen atoms of the two oxazoline heterocycles of thesolid-supported ligand chelate the catalytic metal; and wherein R₁, R₂,R₃ and R₄ are independently —H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, or an optionally substituted aryl;each R₅ and R₆ is independently —H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, or an optionally substituted aryl; Xis O, NH, or S; and wherein SS is a solid resin bead with the provisothat the solid resin bead is not silica. 15: The method of claim 14,wherein each R₁ and R₂ is —CH₃; each R₃, R₄, R₃, and R₆ is —H; X is O;and the Pd⁺² species having the formula PdZ₂ is PdCl₂. 16: The method ofclaim 14, further comprising: separating the solid-supported catalystfrom the palladium cross-coupling product to recover the solid-supportedcatalyst; and reusing the solid-supported catalyst in at least 2reaction cycles with a less than 10% decrease in at least one selectedfrom the group consisting of a turnover number and a turnover frequency.17: The method of claim 14, wherein a molar yield of the palladiumcross-coupling product is at least 75% relative to an initial molaramount of the aryl halide.
 18. (canceled) 19: The method of claim 14,wherein the palladium cross-coupling product comprises less than 100 ppbpalladium, based on the total weight of the palladium cross-couplingproduct or derivatives thereof.
 20. (canceled)